Pyridine derivative

ABSTRACT

Provided is a pyridine derivative represented by formula (I), a prodrug thereof, a pharmaceutically acceptable salt of the pyridine derivative or the prodrug, or a solvate of the pyridine derivative, the prodrug or the pharmaceutically acceptable salt, which is useful for treatment or prophylaxis of diseases associated with URAT1 such as gout, hyperuricemia, hypertension, kidney diseases such as interstitial nephritis, diabetes, arteriosclerosis and Lesch-Nyhan syndrome.

TECHNICAL FIELD

The present invention relates to a pyridine derivative useful as apharmaceutical. More particularly, it relates to a pyridine derivativehaving inhibitory activity against URAT1 and useful in the treatment orprevention of a URAT1-associated disease, such as gout, hyperuricemia,hypertension, renal disease such as interstitial nephritis, diabetes,arteriosclerosis, or Lesch-Nyhan syndrome, or a prodrug thereof, or apharmaceutically acceptable salt thereof, or a solvate thereof.

BACKGROUND ART

Uric acid is the final product of purine metabolism in the liver. Themain route of uric acid excretion is the kidney. Approximatelytwo-thirds of uric acid is excreted in the urine and the remaining isexcreted in feces. Although blood uric acid is maintained in appropriatelevels in healthy individuals, hyperuricemia is induced when anexcessive production of uric acid or a decreased excretion of uric acidoccurs.

Hyperuricemia, in which blood uric acid levels become elevated, is afactor that causes gout and urinary calculus, and furthermore it is saidto contribute to nephropathy and arteriosclerosis. In addition, therehave recently been an increasing number of reports that the higher theblood uric acid level, the higher the incidence rates oflifestyle-related diseases such as metabolic syndrome and hypertension,chronic kidney disease, and the like, and hyperuricemia is beingrecognized to be a risk factor for these diseases. Thus, an improvementin hyperuricemia is expected to lead to improvements in various diseases(Non-Patent Document 1).

Recently, the gene (SLC22A12) encoding a human renal urate transporterhas been identified. The transporter (urate transporter 1, URAT1)encoded by this gene is a 12-transmembrane type molecule belonging tothe OAT family. Its mRNA is specifically expressed in the kidney, andfurther, its localization on apical side of the proximal tubule has beenobserved in human kidney tissue sections. URAT1-mediated uric aciduptake has been shown by experiments using the Xenopus oocyte expressionsystem. Furthermore, it has been reported that probenecid orbenzbromarone, which inhibits URAT1, is useful agent for prevention ortreatment of hyperuricemia, gout, and the like (Non-Patent Document 2).

RELATED ART DOCUMENTS Non-Patent Documents

-   [Non-Patent Document 1] The Guideline Revising Committee of Japanese    Society of Gout and Nucleic Acid Metabolism, ed., Guideline for the    management of hyperuricemia and gout, second edition, Medical Review    (2010).-   [Non-Patent Document 2] Enomoto A. et al., Nature 417, 447-452    (2002).

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

It is an object of the present invention to provide a novel compoundhaving URAT1-inhibitory activity.

Additionally, it is another object of the present invention to providean agent for treatment or prevention of a URAT1-associated disease, suchas gout, hyperuricemia, hypertension, renal disease such as interstitialnephritis, diabetes, arteriosclerosis, or Lesch-Nyhan syndrome,containing the novel compound having URAT1-inhibitory activity as anactive ingredient.

Means of Solving the Problems

As a result of diligent studies with the above objects, the presentinventors have reached the following invention.

That is, the present invention is a pyridine derivative represented bythe following formula (I) or a pharmaceutically acceptable salt thereof,or a solvate thereof:

wherein:A represents a single bond, an oxygen atom, a sulfur atom, NH, or CH₂;R₁ represents a nitrogen atom or CH;one of X₁ to X₅ represents a nitrogen atom, and the remaining fourrepresent CR₂;R₂ each independently represent a hydrogen atom, an alkyl group having 1to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, analkynyl group having 2 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, analkylcarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyl grouphaving 1 to 6 carbon atoms, a nitro group, an amino group, adialkylamino group having 1 to 6 carbon atoms which may optionally forma ring, a formyl group, a hydroxyl group, an alkoxy group having 1 to 6carbon atoms (which may optionally be substituted with one or more of ahydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom),an alkylthio group having 1 to 6 carbon atoms, a phenyl group (which mayoptionally be substituted with one or more of an alkyl group having 1 to6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and ahalogen atom), or a phenoxy group (which may optionally be substitutedwith one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), with the provisothat when two CR₂'s are adjacent, the two R₂'s may optionally be joinedtogether to form a ring;R₃ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms(which may optionally be substituted with one or more of a hydroxylgroup, an amino group, a dialkylamino group having 1 to 6 carbon atomswhich may optionally form a ring, an imidazole ring, a pyrazole ring, apyrrolidine ring, a piperidine ring, a morpholine ring, and a piperazinering (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms and an alkylsulfonyl group having 1 to6 carbon atoms)), an alkenyl group having 2 to 6 carbon atoms, analkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6carbon atoms (which may optionally be substituted with one or more of ahydroxyl group and a halogen atom), an alkylcarbonyl group having 2 to 7carbon atoms, an alkylthio group having 1 to 6 carbon atoms, analkylsulfinyl group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a pyridyl group (which may optionally besubstituted with one or more of an alkyl group having 1 to 6 carbonatoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom),a phenoxy group (which may optionally be substituted with one or more ofan alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6carbon atoms, and a halogen atom), a carboxyl group, or —CO₂R₅;R₄ represents a carboxyl group, a tetrazolyl group, —CONHSO₂R₅, —CO₂R₅,or any of the following substituents:

with the proviso that when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group and when R₄ is a carboxyl group,then R₃ and R₄ may optionally be fused to form a lactone ring;R₅ in R₃ and R₄ each independently represents an alkyl group having 1 to6 carbon atoms;Z represents any of the following substituents, designated Z1 to Z7:

wherein:R₆ and R₇ each independently represent a hydrogen atom, a halogen atom,an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, atrifluoromethoxy group, or a cyano group, with the proviso that the casewhere R₆ and R₇ are simultaneously hydrogen atoms is excluded;R₈ represents a hydrogen atom, a halogen atom, an alkyl group having 1to 6 carbon atoms, or a trifluoromethyl group;R₉ represents a hydrogen atom, a halogen atom, an alkyl group having 1to 6 carbon atoms, or a trifluoromethyl group;R₁₀ represents a hydrogen atom, a halogen atom, an alkyl group having 1to 6 carbon atoms, or a trifluoromethyl group;R₁₁ and R₁₂ each independently represent a hydrogen atom, a halogenatom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethylgroup;R₁₃ and R₁₄ each independently represent a hydrogen atom, a halogenatom, an alkyl group having 1 to 6 carbon atoms, or a trifluoromethylgroup;R₁₅ represents a hydrogen atom, a halogen atom, an alkyl group having 1to 6 carbon atoms, or a trifluoromethyl group;Y represents a hydrogen atom or an alkyl group having 1 to 6 carbonatoms; andW represents a sulfur atom, an oxygen atom, or NR₁₆ (where R₁₆represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,or a benzyl group).

The present invention also provides a prodrug of the pyridine derivativerepresented by the above formula (I) or a pharmaceutically acceptablesalt thereof, or a solvate thereof. In addition, the present inventionprovides: a pharmaceutical composition containing a pyridine derivativerepresented by the above formula (I) or a prodrug thereof, or apharmaceutically acceptable salts thereof, or a solvate thereof, and apharmaceutically acceptable carrier; a URAT1 inhibitor containing as anactive ingredient a pyridine derivative represented by the above formula(I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof,or a solvate thereof; and an agent for treatment or prevention of aURAT1-associated disease, such as gout, hyperuricemia, hypertension,renal disease such as interstitial nephritis, diabetes,arteriosclerosis, or Lesch-Nyhan syndrome, containing as an activeingredient a pyridine derivative represented by the above formula (I) ora prodrug thereof, or a pharmaceutically acceptable salt thereof, or asolvate thereof.

Furthermore, the present invention provides compounds represented by thefollowing formula (II) and formula (III) useful in the synthesis ofpyridine derivatives represented by the above formula (I) or apharmaceutically acceptable salt thereof, or a solvate thereof.

wherein:R₁ and R₃ are as defined in the formula (I);R₁₇ represents a chlorine atom, a bromine atom, or an iodine atom;R₁₈ represents a formyl group or —CO₂R₅;R₅ in R₃ and R₁₈ each independently represents an alkyl group having 1to 6 carbon atoms; andZ represents any of the following substituents, designated Z1 to Z7:

wherein R₆ to R₁₅, Y, and W are as defined in the formula (I), with theproviso that 2-chloro-1-(thiophen-2-ylmethyl)-1H-pyrrole-5-carbaldehyde,ethyl 2-bromo-1-(4-methylbenzyl)-1H-pyrrole-5-carboxylate, and dimethyl2-bromo-1-(2-chlorobenzyl)-1H-imidazole-4,5-dicarboxylate are excluded.

wherein:R₃ is as defined in the formula (I);R₁₉ represents —CO₂R₅;R₅ in R₃ and R₁₉ each independently represents an alkyl group having 1to 6 carbon atoms; andZa represents a 2,5-dichlorobenzyl group, a 3,5-dichlorobenzyl group, a2,5-dimethylbenzyl group, a 2,5-bis(trifluoromethyl)benzyl group, a2-chloro-5-methylbenzyl group, a naphthalen-1-ylmethyl group, a(2-methylnaphthalen-1-yl)methyl group, a (4-methylnaphthalen-1-yl)methylgroup, a (8-methylnaphthalen-1-yl)methyl group, a(8-bromonaphthalen-1-yl)methyl group, a benzo[b]thiophen-3-ylmethylgroup, a (4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

Effects of the Invention

According to the present invention, there is provided a novel pyridinederivative or a prodrug thereof, or a pharmaceutically acceptable saltthereof, or a solvate thereof, useful as an agent for treatment orprevention of a URAT1-associated disease, such as gout, hyperuricemia,hypertension, renal disease such as interstitial nephritis, diabetes,arteriosclerosis, or Lesch-Nyhan syndrome.

MODE FOR CARRYING OUT THE INVENTION

Definitions of the terms for the purpose of the present invention are asfollows.

An alkyl group, for the purpose of the present invention, refers to astraight-chain, branched, or cyclic saturated aliphatic hydrocarbongroup. Specific examples of the alkyl group having 1 to 6 carbon atomscan include, for example, methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, tert-butyl group, pentylgroup, isopentyl group, hexyl group, cyclopropyl group,cyclopropylmethyl group, cyclopentyl group, or cyclohexyl group.

An alkenyl group, for the purpose of the present invention, refers to astraight-chain, branched, or cyclic unsaturated aliphatic hydrocarbongroup containing at least one carbon-carbon double bond. Specificexamples of the alkenyl group having 2 to 6 carbon atoms can include,for example, ethenyl group, 1-propenyl group, 2-propenyl group,2-methyl-1-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenylgroup, 3-methyl-2-butenyl group, 1-pentenyl group, 2-pentenyl group,3-pentenyl group, 4-pentenyl group, 4-methyl-3-pentenyl group, 1-hexenylgroup, 3-hexenyl group, 5-hexenyl group, 1-cyclopenten-1-yl group,3-cyclopenten-1-yl group, 2-cyclohexen-1-yl group, 3-cyclohexen-1-ylgroup, etc.

An alkynyl group, for the purpose of the present invention, refers to astraight-chain or branched unsaturated aliphatic hydrocarbon groupcontaining at least one carbon-carbon triple bond. Specific examples ofthe alkynyl group having 2 to 6 carbon atoms can include, for example,ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group,2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group,3-pentynyl group, 4-pentynyl group, 1-hexynyl group, 2-hexynyl group,3-hexynyl group, 4-hexynyl group, 5-hexynyl group, etc.

An alkylcarbonyl group, for the purpose of the present invention, refersto an aforesaid alkyl group attached through a carbonyl group. Specificexamples of the alkylcarbonyl group having 2 to 7 carbon atoms caninclude, for example, acetyl group, propanoyl group, butanoyl group,isobutanoyl group, sec-butanoyl group, tert-butanoyl group, pentanoylgroup, isopentanoyl group, hexanoyl group, cyclopropylcarbonyl group,cyclohexylcarbonyl group, etc.

An alkylsulfonyl group, for the purpose of the present invention, refersto an aforesaid alkyl group attached through a sulfonyl group. Specificexamples of the alkylsulfonyl group having 1 to 6 carbon atoms caninclude, for example, methylsulfonyl group, ethylsulfonyl group,isopropylsulfonyl group, or cyclopropylsulfonyl group.

An alkylsulfinyl group, for the purpose of the present invention, refersto an aforesaid alkyl group attached through a sulfinyl group. Specificexamples of the alkylsulfinyl group having 1 to 6 carbon atoms caninclude, for example, methylsulfinyl group, ethylsulfinyl group,isopropylsulfinyl group, or cyclopropylsulfinyl group.

An alkoxy group, for the purpose of the present invention, refers to astraight-chain, branched, or cyclic saturated aliphatic hydrocarbonoxygroup. Specific examples of the alkoxy group having 1 to 6 carbon atomscan include, for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, pentyloxy group,isopentyloxy group, hexyloxy group, cyclopropoxy group,cyclopropylmethoxy group, or cyclohexyloxy group.

An alkylthio group, for the purpose of the present invention, refers toa straight-chain, branched, or cyclic saturated aliphatichydrocarbonsulfide group. Specific examples of the alkylthio grouphaving 1 to 6 carbon atoms can include, for example, methylthio group,ethylthio group, propylthio group, isopropylthio group, butylthio group,isobutylthio group, pentylthio group, isopentylthio group, hexylthiogroup, cyclopropylthio group, cyclopropylmethylthio group, orcyclohexylthio group.

A dialkylamino group, for the purpose of the present invention, refersto an amino group substituted with two identical or different aforesaidalkyl groups. A dialkylamino group having 1 to 6 carbon atoms, for thepurpose of the present invention, refers to an amino group substitutedwith two identical or different alkyl groups each having 1 to 6 carbonatoms. A dialkylamino group, for the purpose of the present invention,may optionally form a ring with the alkyl groups. Specific examples ofthe dialkylamino groups having 1 to 6 carbon atoms which may optionallyform a ring can include, for example, dimethylamino group, diethylaminogroup, pyrrolidin-1-yl group, or piperidin-1-yl group.

A halogen atom, for the purpose of the present invention, refers to afluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

For the purpose of the present invention, “when two CR₂'s are adjacent,the two R₂'s are joined together to form a ring” means that two R₂'s arejoined together and taken together with the carbon atoms to which theyare attached on the pyridine ring to form a nonaromatic or aromaticring. The joining of two R₂'s to form a ring results in the formation ofa bicyclic ring in which the ring is fused to a pyridine ring. Suchnonaromatic or aromatic ring may be a hydrocarbon ring or a heterocyclehaving an oxygen atom, a nitrogen atom, or a sulfur atom as aconstituent atom.

For the purpose of the present invention, “substituted with an imidazolering, a pyrazole ring, a pyrrolidine ring, a piperidine ring, amorpholine ring, or a piperazine ring” refers to being substituted withany of the groups derived from each of these rings by the removal of onehydrogen atom therefrom.

In the above formula (I), A represents a single bond, an oxygen atom, asulfur atom, NH, or CH₂. Preferably, A is a single bond or an oxygenatom, and more preferably a single bond.

R₁ represents a nitrogen atom or CH, and preferably a nitrogen atom.

One of X₁ to X₅ represents a nitrogen atom, and the remaining fourrepresent CR₂. Preferably, X₁ or X₂ is a nitrogen atom, and morepreferably X₂ is a nitrogen atom.

R₂ each independently represent a hydrogen atom, an alkyl group having 1to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, analkynyl group having 2 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, analkylcarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyl grouphaving 1 to 6 carbon atoms, a nitro group, an amino group, adialkylamino group having 1 to 6 carbon atoms which may optionally forma ring, a formyl group, a hydroxyl group, an alkoxy group having 1 to 6carbon atoms (which may optionally be substituted with one or more of ahydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom),an alkylthio group having 1 to 6 carbon atoms, a phenyl group (which mayoptionally be substituted with one or more of an alkyl group having 1 to6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and ahalogen atom), or a phenoxy group (which may optionally be substitutedwith one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), with the provisothat when two CR₂s are adjacent, the two R₂'s may optionally be joinedtogether to form a ring. The ring formed by two adjacent CR₂'s ispreferably an aromatic hydrocarbon ring, and more preferably a benzenering. Preferably, R₂ is a hydrogen atom, an alkyl group having 1 to 6carbon atoms, a halogen atom, a trifluoromethyl group, a difluoromethylgroup, a cyano group, a nitro group, a dialkylamino group having 1 to 6carbon atoms which may optionally form a ring, a hydroxyl group, analkoxy group having 1 to 6 carbon atoms (which may optionally besubstituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom). More preferably, R₂ is a hydrogen atom, amethyl group, an ethyl group, a cyclopropyl group, a methoxy group, anethoxy group, a methylthio group, a fluorine atom, a chlorine atom, abromine atom, a cyano group, a hydroxyl group, a pyrrolidin-1-yl group,a trifluoromethyl group, a difluoromethyl group, a nitro group, a phenylgroup, or a phenoxy group. Even more preferably, R₂ is a hydrogen atom,a methyl group, an ethyl group, a cyclopropyl group, a fluorine atom, achlorine atom, a bromine atom, a methoxy group, an ethoxy group, amethylthio group, a trifluoromethyl group, a difluoromethyl group, anitro group, or a phenyl group.

When three of the four CR₂'s are CH, preferred positions of theremaining CR₂ can include X₄. When three of the four CR₂'s are CH, thecombination of the positions of a nitrogen atom and the remaining CR₂ ispreferably the combination in which X₂ is a nitrogen atom and X₄ is CR₂.

When two of the four CR₂'s are CH, combinations of the positions of anitrogen atom and the remaining CR₂'s can include, for example, thecombination in which X₂ is a nitrogen atom and X₁ and X₃ are CR₂, andthe combination in which X₂ is a nitrogen atom and X₃ and X₄ are CR₂.

R₃ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms(which may optionally be substituted with one or more of a hydroxylgroup, an amino group, a dialkylamino group having 1 to 6 carbon atomswhich may optionally form a ring, an imidazole ring, a pyrazole ring, apyrrolidine ring, a piperidine ring, a morpholine ring, and a piperazinering (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms and an alkylsulfonyl group having 1 to6 carbon atoms)), an alkenyl group having 2 to 6 carbon atoms, analkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6carbon atoms (which may optionally be substituted with one or more of ahydroxyl group and a halogen atom), an alkylcarbonyl group having 2 to 7carbon atoms, an alkylthio group having 1 to 6 carbon atoms, analkylsulfinyl group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a pyridyl group (which may optionally besubstituted with one or more of an alkyl group having 1 to 6 carbonatoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom),a phenoxy group (which may optionally be substituted with one or more ofan alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6carbon atoms, and a halogen atom), a carboxyl group, or —CO₂R₅.Preferably, R₃ is a hydrogen atom, an alkyl group having 1 to 6 carbonatoms (which may optionally be substituted with one or more of ahydroxyl group, an amino group, a dialkylamino group having 1 to 6carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkoxy group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅. Morepreferably, R₃ is a hydrogen atom, a methyl group, an ethyl group, anisopropyl group, a cyclopropyl group, a trifluoromethyl group, adifluoromethyl group, a chlorine atom, a bromine atom, an iodine atom, amethoxy group, a methylthio group, an ethylthio group, a cyano group, aphenyl group, a carboxyl group, —CO₂R₅, a hydroxymethyl group, a2-hydroxypropan-2-yl group, a 3-hydroxypentan-3-yl group, or amorpholin-4-ylmethyl group.

R₄ represents a carboxyl group, a tetrazolyl group, —CONHSO₂R₅, or—CO₂R₅, or any of the following substituents:

with the proviso that when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group and when R₄ is a carboxyl group,then R₃ and R₄ may optionally be fused to form a lactone ring.Preferably, R₄ is a carboxyl group (which, when R₃ is an alkyl grouphaving 1 to 6 carbon atoms substituted with a hydroxyl group, mayoptionally be fused with R₃ to form a lactone ring), a tetrazolyl group,—CONHSO₂CH₃, —CONHSO₂-cyclopropyl, or —CO₂R₅.

R₅ in R₃ and R₄ each independently represents an alkyl group having 1 to6 carbon atoms.

Further, Z in the above formula (I) represents any of the followingsubstituents, designated Z1 to Z7.

In Z1, R₆ and R₇ each independently represent a hydrogen atom, a halogenatom, an alkyl group having 1 to 6 carbon atoms, a trifluoromethylgroup, a trifluoromethoxy group, or a cyano group, with the proviso thatthe case where R₆ and R₇ are simultaneously hydrogen atoms is excluded.Preferably, R₆ and R₇ are each a methyl group, a fluorine atom, achlorine atom, a bromine atom, or a trifluoromethyl group. Morepreferably, R₆ and R₇ are each a chlorine atom, a methyl group, or atrifluoromethyl group. Preferred substitution positions for R₆ and R₇ onthe benzene ring are 2,5-disubstitution and 3,5-disubstitution, and themore preferred is 2,5-disubstitution. A preferred combination of R₆ andR₇ with their substitution positions on the benzene ring is 2,5-dichlorosubstitution, 3,5-dichloro substitution, 2,5-dimethyl substitution,2,5-bis(trifluoromethyl) substitution, or 2-chloro-5-methylsubstitution.

Y represents a hydrogen atom or an alkyl group having 1 to 6 carbonatoms. Preferably, Y is a hydrogen atom.

In Z2, R₈ represents a hydrogen atom, a halogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or a trifluoromethyl group. A preferredcombination of R₈ with its substitution position on the naphthalene ringis a hydrogen atom, a 2-methyl group, a 4-methyl group, an 8-methylgroup, or an 8-bromo group.

In Z3, R₉ represents a hydrogen atom, a halogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or a trifluoromethyl group. W represents asulfur atom, an oxygen atom, or NR₁₆ (where R₁₆ represents a hydrogenatom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group), andpreferably a sulfur atom.

A preferred combination of R₉ with its substitution position on thebenzothiophene, benzofuran, or indole ring is a hydrogen atom, a4-methyl group, a 4-chloro group, a 4-bromo group, a 4-trifluoromethylgroup, a 5-methyl group, a 5-chloro group, or a 5-trifluoromethyl group.

In Z4, R₁₀ represents a hydrogen atom, a halogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or a trifluoromethyl group. W represents asulfur atom, an oxygen atom, or NR₁₆ (where R₁₆ represents a hydrogenatom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group), andpreferably a sulfur atom. A preferred combination of R₁₀ with itssubstitution position on the benzothiophene, benzofuran, or indole ringis a hydrogen atom or a 5-fluoro group.

In Z5, R₁₁ and R₁₂ each independently represent a hydrogen atom, ahalogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group. W represents a sulfur atom, an oxygen atom, orNR₁₆ (where R₁₆ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms, or a benzyl group), and preferably a sulfur atom. Apreferred combination of R₁₁ and R₁₂ with their substitution positionson the thiophene, furan, or pyrrole ring is 2,5-dichloro substitution.

In Z6, R₁₃ and R₁₄ each independently represent a hydrogen atom, ahalogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group. W represents a sulfur atom, an oxygen atom, orNR₁₆ (where R₁₆ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms, or a benzyl group), and preferably a sulfur atom. Apreferred combination of R₁₃ and R₁₄ with their substitution positionson the thiophene, furan, or pyrrole ring is 2,4-dichloro substitution.

In Z7, R₁₅ represents a hydrogen atom, a halogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or a trifluoromethyl group. Preferably, R₁₅is a hydrogen atom.

Preferred among Z1 to Z7 are Z1 to Z6, and more preferred are Z1 to Z4.

Preferred Z is, in particular, for example, a 2,5-dichlorobenzyl group,a 3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group,and more preferred Z is, for example, a 2,5-dichlorobenzyl group, a2,5-dimethylbenzyl group, a naphthalen-1-ylmethyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, or abenzo[b]thiophen-7-ylmethyl group.

Preferred combinations of the A, X₁-X₅, R₁-R₄, and Z present in theformula (I) according to the present invention can include the followingcombinations 1) to 11).

1) A is a single bond; R₁ is a nitrogen atom; X₁ is a nitrogen atom; X₄is CR₂, and X₂, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino groupoptionally forming a ring with the alkyl groups each having 1 to 6carbon atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbonatoms (which may optionally be substituted with one or more of ahydroxyl group, a phenyl group, a cyclohexyl group, and a halogen atom),an alkylthio group having 1 to 6 carbon atoms, a phenyl group (which mayoptionally be substituted with one or more of an alkyl group having 1 to6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and ahalogen atom), or a phenoxy group (which may optionally be substitutedwith one or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom); R₃ is a hydrogenatom, an alkyl group having 1 to 6 carbon atoms (which may optionally besubstituted with one or more of a hydroxyl group, an amino group, adialkylamino group having 1 to 6 carbon atoms which may optionally forma ring, an imidazole ring, a pyrazole ring, a pyrrolidine ring, apiperidine ring, a morpholine ring, and a piperazine ring (which mayoptionally be substituted with one or more of an alkyl group having 1 to6 carbon atoms and an alkylsulfonyl group having 1 to 6 carbon atoms)),an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1to 6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a phenyl group (which mayoptionally be substituted with one or more of an alkyl group having 1 to6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and ahalogen atom), a carboxyl group, or —CO₂R₅; R₄ is a carboxyl group(which, when R₃ is an alkyl group having 1 to 6 carbon atoms substitutedwith a hydroxyl group, may optionally be fused with R₃ to form a lactonering), a tetrazolyl group, —CONHSO₂CH₃, —CONHSO₂-cyclopropyl, or —CO₂R₅;and Z is a 2,5-dichlorobenzyl group, a 3,5-dichlorobenzyl group, a2,5-dimethylbenzyl group, a 2,5-bis(trifluoromethyl)benzyl group, a2-chloro-5-methylbenzyl group, a naphthalen-1-ylmethyl group, a(2-methylnaphthalen-1-yl)methyl group, a (4-methylnaphthalen-1-yl)methylgroup, a (8-methylnaphthalen-1-yl)methyl group, a(8-bromonaphthalen-1-yl)methyl group, a benzo[b]thiophen-3-ylmethylgroup, a (4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

2) A is a single bond; R₁ is a nitrogen atom; X₂ is a nitrogen atom; X₄is CR₂, and X₁, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino grouphaving 1 to 6 carbon atoms which may optionally form a ring, a hydroxylgroup, an alkoxy group having 1 to 6 carbon atoms (which may optionallybe substituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom); R₃ is a hydrogen atom, an alkyl group having1 to 6 carbon atoms (which may optionally be substituted with one ormore of a hydroxyl group, an amino group, a dialkylamino group having 1to 6 carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkoxy group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅; R₄ is acarboxyl group (which, when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group, may optionally be fused with R₃to form a lactone ring), a tetrazolyl group, —CONHSO₂CH₃,—CONHSO₂-cyclopropyl, or —CO₂R₅; and Z is a 2,5-dichlorobenzyl group, a3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

3) A is a single bond; R₁ is CH; X₁ is a nitrogen atom; X₄ is CR₂, andX₂, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl group having 1 to6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino grouphaving 1 to 6 carbon atoms which may optionally form a ring, a hydroxylgroup, an alkoxy group having 1 to 6 carbon atoms (which may optionallybe substituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom); R₃ is a hydrogen atom, an alkyl group having1 to 6 carbon atoms (which may optionally be substituted with one ormore of a hydroxyl group, an amino group, a dialkylamino group having 1to 6 carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkoxy group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅; R₄ is acarboxyl group (which, when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group, may optionally be fused with R₃to form a lactone ring), a tetrazolyl group, —CONHSO₂CH₃,—CONHSO₂-cyclopropyl, or —CO₂R₅; and Z is a 2,5-dichlorobenzyl group, a3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

4) A is a single bond; R₁ is CH; X₂ is a nitrogen atom; X₄ is CR₂, andX₁, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl group having 1 to6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino grouphaving 1 to 6 carbon atoms which may optionally form a ring, a hydroxylgroup, an alkoxy group having 1 to 6 carbon atoms (which may optionallybe substituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom); R₃ is a hydrogen atom, an alkyl group having1 to 6 carbon atoms (which may optionally be substituted with one ormore of a hydroxyl group, an amino group, a dialkylamino group having 1to 6 carbon atoms which may optionally form a ring, a pyrazole ring, apyrrolidine ring, a piperidine ring, a morpholine ring, and a piperazinering (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms and an alkylsulfonyl group having 1 to6 carbon atoms)), an alkoxy group having 1 to 6 carbon atoms, analkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅; R₄ is acarboxyl group (which, when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group, may optionally be fused with R₃to form a lactone ring), a tetrazolyl group, —CONHSO₂CH₃,—CONHSO₂-cyclopropyl, or —CO₂R₅; and Z is a 2,5-dichlorobenzyl group, a3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

5) A is an oxygen atom; R₁ is a nitrogen atom; X₁ is a nitrogen atom; X₄is CR₂, and X₂, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino grouphaving 1 to 6 carbon atoms which may optionally form a ring, a hydroxylgroup, an alkoxy group having 1 to 6 carbon atoms (which may optionallybe substituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom); R₃ is a hydrogen atom, an alkyl group having1 to 6 carbon atoms (which may optionally be substituted with one ormore of a hydroxyl group, an amino group, a dialkylamino group having 1to 6 carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkoxy group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅; R₄ is acarboxyl group (which, when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group, may optionally be fused with R₃to form a lactone ring), a tetrazolyl group, —CONHSO₂CH₃,—CONHSO₂-cyclopropyl, or —CO₂R₅; and Z is a 2,5-dichlorobenzyl group, a3,5-di chlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinoline-8-ylmethylgroup.

6) A is an oxygen atom; R₁ is a nitrogen atom; X₂ is a nitrogen atom; X₄is CR₂, and X₁, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino grouphaving 1 to 6 carbon atoms which may optionally form a ring, a hydroxylgroup, an alkoxy group having 1 to 6 carbon atoms (which may optionallybe substituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom); R₃ is a hydrogen atom, an alkyl group having1 to 6 carbon atoms (which may optionally be substituted with one ormore of a hydroxyl group, an amino group, a dialkylamino group having 1to 6 carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkoxy group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅; R₄ is acarboxyl group (which, when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group, may optionally be fused with R₃to form a lactone ring), a tetrazolyl group, —CONHSO₂CH₃,—CONHSO₂-cyclopropyl, or —CO₂R₅; and Z is a 2,5-dichlorobenzyl group, a3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

7) A is an oxygen atom; R₁ is CH; X₁ is a nitrogen atom; X₄ is CR₂, andX₂, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl group having 1 to6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino grouphaving 1 to 6 carbon atoms which may optionally form a ring, a hydroxylgroup, an alkoxy group having 1 to 6 carbon atoms (which may optionallybe substituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom); R₃ is a hydrogen atom, an alkyl group having1 to 6 carbon atoms (which may optionally be substituted with one ormore of a hydroxyl group, an amino group, a dialkylamino group having 1to 6 carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkoxy group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅; R₄ is acarboxyl group (which, when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group, may optionally be fused with R₃to form a lactone ring), a tetrazolyl group, —CONHSO₂CH₃,—CONHSO₂-cyclopropyl, or —CO₂R₅; and Z is a 2,5-dichlorobenzyl group, a3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

8) A is an oxygen atom; R₁ is CH; X₂ is a nitrogen atom; X₄ is CR₂, andX₁, X₃, and X₅ are CH; R₂ is a hydrogen atom, an alkyl group having 1 to6 carbon atoms, a halogen atom, a trifluoromethyl group, adifluoromethyl group, a cyano group, a nitro group, a dialkylamino grouphaving 1 to 6 carbon atoms which may optionally form a ring, a hydroxylgroup, an alkoxy group having 1 to 6 carbon atoms (which may optionallybe substituted with one or more of a hydroxyl group, a phenyl group, acyclohexyl group, and a halogen atom), an alkylthio group having 1 to 6carbon atoms, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), or a phenoxygroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom); R₃ is a hydrogen atom, an alkyl group having1 to 6 carbon atoms (which may optionally be substituted with one ormore of a hydroxyl group, an amino group, a dialkylamino group having 1to 6 carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkoxy group having 1 to 6 carbonatoms, an alkylthio group having 1 to 6 carbon atoms, a halogen atom, atrifluoromethyl group, a difluoromethyl group, a cyano group, a phenylgroup (which may optionally be substituted with one or more of an alkylgroup having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbonatoms, and a halogen atom), a carboxyl group, or —CO₂R₅; R₄ is acarboxyl group (which, when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group, may optionally be fused with R₃to form a lactone ring), a tetrazolyl group, —CONHSO₂CH₃,—CONHSO₂-cyclopropyl, or —CO₂R₅; and Z is a 2,5-dichlorobenzyl group, a3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

9) In 1) to 8) above, R₂ is a hydrogen atom, a methyl group, an ethylgroup, a cyclopropyl group, a fluorine atom, a chlorine atom, a bromineatom, a methoxy group, an ethoxy group, a methylthio group, atrifluoromethyl group, a difluoromethyl group, a nitro group, or aphenyl group.

10) In 1) to 9) above, R₃ is a hydrogen atom, a methyl group, an ethylgroup, an isopropyl group, a cyclopropyl group, a trifluoromethyl group,a difluoromethyl group, a chlorine atom, a bromine atom, an iodine atom,a methoxy group, a methylthio group, an ethylthio group, a cyano group,a phenyl group, a carboxyl group, —CO₂R₅, a hydroxymethyl group, a2-hydroxypropan-2-yl group, a 3-hydroxypentan-3-yl group, or amorpholin-4-ylmethyl group.

11) In 1) to 10) above, Z is a 2,5-dichlorobenzyl group, a2,5-dimethylbenzyl group, a naphthalen-1-ylmethyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, or abenzo[b]thiophen-7-ylmethyl group.

Synthetic intermediates useful in the synthesis of a pyridine derivativerepresented by the above formula (I) or a pharmaceutically acceptablesalt thereof, or a solvate thereof, can include compounds represented bythe following formula (II) and formula (III).

wherein:R₁ and R₃ are as defined in the formula (I);R₁₇ represents a chlorine atom, a bromine atom, or an iodine atom;R₁₈ represents a formyl group or —CO₂R₅;R₅ in R₃ and R₁₈ each independently represents an alkyl group having 1to 6 carbon atoms; and

Z represents any of the following substituents, designated Z1 to Z7:

wherein R₆ to R₁₅, Y, and W are as defined in the formula (I), with theproviso that 2-chloro-1-(thiophen-2-ylmethyl)-1H-pyrrole-5-carbaldehyde,ethyl 2-bromo-1-(4-methylbenzyl)-1H-pyrrole-5-carboxylate, and dimethyl2-bromo-1-(2-chlorobenzyl)-1H-imidazole-4,5-dicarboxylate are excluded.

Preferably R₃ is a hydrogen atom, an alkyl group having 1 to 6 carbonatoms (which may optionally be substituted with one or more hydroxylgroups), a halogen atom, a trifluoromethyl group, or —CO₂R₅. Morepreferably R₃ is a hydrogen atom, a methyl group, an ethyl group, anisopropyl group, a cyclopropyl group, a trifluoromethyl group, achlorine atom, a bromine atom, or —CO₂R₅.

Preferred R₁₇ is a bromine atom or an iodine atom.

Preferred R₁₈ is a formyl group, —CO₂CH₃, or —CO₂C₂H₅.

wherein:R₃ is as defined in the formula (I);R₁₉ represents —CO₂R₅;R₅ in R₃ and R₁₉ each independently represents an alkyl group having 1to 6 carbon atoms; andZa represents a 2,5-dichlorobenzyl group, a 3,5-dichlorobenzyl group, a2,5-dimethylbenzyl group, a 2,5-bis(trifluoromethyl)benzyl group, a2-chloro-5-methylbenzyl group, a naphthalen-1-ylmethyl group, a(2-methylnaphthalen-1-yl)methyl group, a (4-methylnaphthalen-1-yl)methylgroup, a (8-methylnaphthalen-1-yl)methyl group, a(8-bromonaphthalen-1-yl)methyl group, a benzo[b]thiophen-3-ylmethylgroup, a (4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.

Preferably R₃ is a hydrogen atom, an alkyl group having 1 to 6 carbonatoms (which may optionally be substituted with one or more hydroxylgroups), a halogen atom, a trifluoromethyl group, or —CO₂R₅. Morepreferably R₃ is a hydrogen atom, a methyl group, an ethyl group, anisopropyl group, a cyclopropyl group, a trifluoromethyl group, achlorine atom, a bromine atom, or —CO₂R₅.

Preferred R₁₉ is —CO₂CH₃ or —CO₂C₂H₅

Preferred Za is a 2,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group,a naphthalen-1-ylmethyl group, a (4-chlorobenzo[b]thiophen-3-yl)methylgroup, or benzo[b]thiophen-7-ylmethyl group.

Specific examples of the pyridine derivative represented by the formula(I) of the present invention can include the following compounds.

Com- pound No. Structure [Chemical Formula 13] A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

[Chemical Formula 14] A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

[Chemical Formula 15] A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

[Chemical Formula 16] A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

[Chemical Formula 17] A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

[Chemical Formula 18] A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

A72

[Chemical Formula 19] A73

A74

A75

A76

A77

A78

A79

A80

A81

A82

A83

A84

[Chemical Formula 20] A85

A86

A87

A88

A89

A90

A91

A92

A93

A94

A95

A96

[Chemical Formula 21] A97

A98

A99

A100

A101

A102

A103

A104

A105

A106

A107

A108

[Chemical Formula 22] A109

A110

A111

A112

A113

A114

A115

A116

A117

A118

A119

A120

[Chemical Formula 23] A121

A122

A123

A124

A125

A126

A127

A128

A129

A130

A131

A132

[Chemical Formula 24] A133

A134

A135

A136

A137

A138

A139

A140

A141

A142

A143

A144

[Chemical Formula 25] A145

A146

A147

A148

A149

A150

A151

A152

A153

A154

A155

A156

[Chemical Formula 26] A157

A158

A159

A160

A161

A162

A163

A164

A165

A166

A167

A168

[Chemical Formula 27] A169

A170

A171

A172

A173

A174

A175

A176

A177

A178

A179

A180

[Chemical Formula 28] A181

A182

A183

A184

A185

A186

A187

A188

A189

A190

A191

A192

[Chemical Formula 29] A193

A194

A195

A196

A197

A198

A199

A200

A201

A202

A203

A204

[Chemical Formula 30] A205

A206

A207

A208

A209

A210

A211

A212

A213

A214

A215

A216

[Chemical Formula 31] A217

A218

A219

A220

A221

A222

A223

A224

A225

A226

A227

A228

[Chemical Formula 32] A229

A230

A231

A232

A233

A234

A235

A236

A237

A238

A239

A240

[Chemical Formula 33] A241

A242

A243

A244

A245

A246

A247

A248

A249

A250

A251

A252

[Chemical Formula 34] A253

A254

A255

A256

A257

A258

A259

A260

A261

A262

A263

A264

[Chemical Formula 35] A265

A266

A267

A268

A269

A270

A271

A272

A273

A274

A275

A276

[Chemical Formula 36] A277

A278

A279

A280

A281

A282

B1

B2

B3

B4

B5

B6

[Chemical Formula 37] B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

[Chemical Formula 38] B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

[Chemical Formula 39] B31

B32

B33

B34

B35

Of these, preferred compounds are those listed in the tables below.

TABLE 1 Compound No. Compound Name A11-(2,5-dimehylbenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A24-methyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A3 ethyl4-methyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate A64-methyl-2-(pyridin-3-yl)-1-((4-(trifluoromethyl)benzo[b]thiophen-3-yl)-methyl)-1H-imidazole-5-carboxylic acid A71-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A81-((4-bromobenzo[b]thiophen-3-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A94-chloro-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A10 4-ethyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5- carboxylic acid A114-cyclopropyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A131-(2,5-dichlorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A141-(2,5-dichlorobenzyl)-4-ethyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A154-cyclopropyl-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A174-methyl-1-((4-methylnaphthalen-1-yl)methyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A184-cyclopropyl-1-((4-methylnaphthalen-1-yl)methyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A191-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid A221-(benzo[b]thiophen-3-ylmethyl)-2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid A234-chloro-1-((4-methylnaphthalen-1-yl)methyl)-2-(pyridin-3 -yl)-1H-imidazole-5-carboxylic acid A244-isopropyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A254-isopropyl-1-((4-methylnaphthalen-1-yl)methyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A261-(2,5-dichlorobenzyl)-4-isopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A271-((4-chlorobenzo[b]thiophen-3-yl)methyl)-2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid

TABLE 2 Compound No. Compound Name A311-((4-bromobenzo[b]thiophen-3-yl)methyl)-2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid A331-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-cyclopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A341-((4-bromobenzo[b]thiophen-3-yl)methyl)-4-cyclopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A354-cyclopropyl-2-(pyridin-3-yl)-1-((4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl)-1H-imidazole-5-carboxylic acid A361-(benzo[b]thiophen-3-ylmethyl)-4-cyclopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A371-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-isopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A381-((4-bromobenzo[b]thiophen-3-yl)methyl)-4-isopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A394-isopropyl-2-(pyridin-3-yl)-1-((4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl)-1H-imidazole-5-carboxylic acid A401-(benzo[b]thiophen-3-ylmethyl)-4-isopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A411-(2-chloro-5-fluorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A421-(5-chloro-2-fluorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A431-(2-chloro-5-(trifluoromethyl)benzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A441-(5-chloro-2-(trifluoromethyl)benzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A451-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acidA461-(2,5-bis(trifluoromethyl)benzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A541-(2-bromobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid A551-(3-bromobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid A671-(2,5-dichlorobenzyl)-4-methyl-2-(quinolin-3-yl)-1H-imidazole-5-carboxylic acid A681-(3,4-dichlorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A701-(2,3-dichlorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid

TABLE 3 A711-(3,5-dichlorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A761-(3-chloro-5-fluorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A771-(2,4-dichlorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A781-(2-chloro-5-methylbenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A791-((2,5-dichlorothiophen-3-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A801-((2,4-dichlorothiophen-5-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A811-(benzo[b]thiophen-7-ylmethyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A821-(benzo[b]thiophen-7-ylmethyl)-4-cyclopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A831-(benzo[b]thiophen-7-ylmethyl)-4-isopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A841-(benzo[b]thiophen-7-ylmethyl)-2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid A851-((5-fluorobenzo[b]thiophen-7-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A864-cyclopropyl-1-((5-fluorobenzo[b]thiophen-7-yl)methyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A884-chloro-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A894-bromo-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A901-(2,5-dichlorobenzyl)-4-iodo-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid A911-(2,5-dichlorobenzyl)-4-phenyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A921-(2,5-dichlorobenzyl)-4-(3-fluorophenyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A931-(2,5-dichlorobenzyl)-4-(4-fluorophenyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A941-(2,5-dichlorobenzyl)-2,4-di(pyridin-3-yl)-1H-imidazole-5-carboxylicacid A961-(2,5-dichlorobenzyl)-4-methoxy-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A981-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-(2,2,2-trifluoroethoxy)-1H-imidazole-5-carboxylic acid

TABLE 4 Compound No. Compound Name A991-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-(p-tolyloxy)-1H-imidazole-5-carboxylic acid A1001-(2,5-dichlorobenzyl)-4-(4-fluorophenoxy)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1014-cyano-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1021-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-vinyl-1H-imidazole-5-carboxylic acid A1034-(1-cyclopenten-1-yl)-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1041-(2,5-dichlorobenzyl)-4-(methylthio)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1051-(2,5-dichlorobenzyl)-4-(ethylthio)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1081-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1091-(2,5-dichlorobenzyl)-4-(3-hydroxypentan-3-yl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1103-(1-(2,5-dichlorobenzyl)-5-(1H-tetrazol-5-yl)-1H-imidazol-2-yl)pyridineA117 1-(benzo[b]thiophen-7-ylmethyl)-4-cyclopropyl-N-(methylsulfonyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxamide A1181-(benzo[b]thiophen-7-ylmethyl)-4-cyclopropyl-N-(cyclopropylsulfonyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxamide A1192-(5-fluoropyridin-3-yl)-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1212-(5-chloropyridin-3-yl)-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1304-methyl-1-(naphthalen-1-ylmethyl)-2-(5-phenoxypyridin-3-yl)-1H-imidazole-5-carboxylic acid A1321-(benzo[b]thiophen-3-ylmethyl)-2-(5-chloropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1331-(benzo[b]thiophen-3-ylmethyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1341-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1352-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1361-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid

TABLE 5 Compound No. Compound Name A1372-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid A1384-methyl-1-(naphthalen-1-ylmethyl)-2-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1391-(2,5-dichlorobenzyl)-4-methyl-2-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1401-(2,5-dichlorobenzyl)-4-(trifluoromethyl)-2-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1411-((4-chlorobenzo[b]thiophen-3-yl)methyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1421-((4-chlorobenzo[b]thiophen-3-yl)methyl)-2-(5-chloropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1431-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-2-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1442-(5-chloropyridin-3-yl)-4-isopropyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1452-(5-chloropyridin-3-yl)-4-cyclopropyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1462-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-isopropyl-1H-imidazole-5-carboxylic acid A1472-(5-chloropyridin-3-yl)-4-cyclopropyl-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylic acid A1484-ethyl-2-(5-fluoropyridin-3-yl)-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1492-(5-chloropyridin-3-yl)-4-ethyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1501-(2,5-dichlorobenzyl)-4-ethyl-2-(5-fluoropyridin-3-yl)-1H-imidazole-5-carboxylic acid A1512-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-ethyl-1H-imidazole-5-carboxylic acid A1522-(5-fluoropyridin-3-yl)-4-isopropyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1534-cyclopropyl-2-(5-fluoropyridin-3-yl)-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1541-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-4-isopropyl-1H-imidazole-5-carboxylic acid A1554-cyclopropyl-1-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-1H-imidazole-5-carboxylic acid A1561-(2,5-dichlorobenzyl)-4-methyl-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid

TABLE 6 Compound No. Compound Name A1571-(2,5-dichlorobenzyl)-2-(5-methoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1582-(5-cyanopyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1591-(2,5-dichlorobenzyl)-4-methyl-2-(6-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A1601-(2,5-dichlorobenzyl)-2-(2-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1611-(2,5-dichlorobenzyl)-2-(6-methoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1621-(2,5-dichlorobenzyl)-2-(2-methoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1642-(6-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1661-(2,5-dichlorobenzyl)-4-methyl-2-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1671-(2,5-dichlorobenzyl)-4-methyl-2-(5-nitropyridin-3-yl)-1H-imidazole-5-carboxylic acid A1682-(5-cyclopropylpyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1692-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylic acid A1701-(2,5-bis(trifluoromethyl)benzyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1711-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-1H-imidazole-5-carboxylic acid A1721-(2,5-dichlorobenzyl)-2-(5-hydroxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1731-(2,5-bis(trifluoromethyl)benzyl)-2-(5-chloropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1741-(2,5-dichlorobenzyl)-2-(5-ethoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1751-(2,5-dichlorobenzyl)-2-(5-isopropoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1761-(2,5-dichlorobenzyl)-4-methyl-2-(5-phenylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A1772-(5-bromopyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1781-(2,5-dimethylbenzyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid

TABLE 7 Compound No. Compound Name A1792-(5-chloropyridin-3-yl)-1-(2,5-dimethylbenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1801-(2,5-dimethylbenzyl)-4-methyl-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A1811-(2,5-dichlorobenzyl)-2-(5-ethylpyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1821-(2,5-dichlorobenzyl)-4-methyl-2-(5-(methylthio)pyridin-3-yl)-1H-imidazole-5-carboxylic acid A1832-(5-acetylpyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1851-(2,5-dichlorobenzyl)-4-methyl-2-(5-propoxypyridin-3-yl)-1H-imidazole-5-carboxylic acid A1881-(2,5-dichlorobenzyl)-2-(5-isobutoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A1892-(5-(cyclohexylmethoxy)pyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1902-(5-(benzyloxy)pyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A1912-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylic acid A1922-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((dimethylamino)methyl)-1H-imidazole-5-carboxylic acid A1932-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((diethylamino)methyl)-1H-imidazole-5-carboxylic acid A1942-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(pyrrolidin-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1952-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(piperidin-1-ylmethyl)-1H-imidazole-5-carboxylic acid A1962-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(morpholinomethyl)-1H-imidazole-5-carboxylic acid A1972-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((4-methylpiperazine-1-yl)methyl)-1H-imidazole-5-carboxylic acid A1994-((1H-imidazol-1-yl)methyl)-2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylic acid A2004-((1H-pyrazol-1-yl)methyl)-2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylic acid A2022-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((4-propylpiperazin-1-yl)methyl)-1H-imidazole-5-carboxylic acid

TABLE 8 Compound No. Compound Name A2032-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-imidazole-5-carboxylic acid A2042-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)-1H-imidazole-5-carboxylic acid A2052-(5-bromopyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylic acid A2061-(2,5-dichlorobenzyl)-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A2072-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylic acid A2081-(2,5-dichlorobenzyl)-2-(5-(difluoromethyl)pyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2092-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-ethynyl-1H-imidazole-5-carboxylic acid A2102-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-4,5-dicarboxylic acid A2112-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(1-hydroxyethyl)-1H-imidazole-5-carboxylic acid A2121-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-4-(2-hydroxypropan-2-yl)-1H-imidazole-5-carboxylic acid A2132-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-1H-imidazole-5-carboxylic acid A2141-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-2-(5-methylpyridine-3-yl)-1H-imidazole-5-carboxylic acid A2151-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-4-(3-hydroxypentan-3-yl)-1H-imidazole-5-carboxylic acid A2162-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(3-hydroxypentane-3-yl)-1H-imidazole-5-carboxylic acid A2171-(2,5-dichlorobenzyl)-4-(3-hydroxypentan-3-yl)-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A2184-acetyl-2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylic acid A2194-chloro-1-(2,5-dichlorobenzyl)-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid

TABLE 9 A2204-chloro-2-(5-chloropyridine-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylic acid A2212-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-furo[3,4-d]imidazole-6(4H)-one A2232-(5-chloropyridin-3-yl)-1-(1-(2,5-dichlorophenyl)ethyl)-4-methyl-1H-imidazole-5-carboxylic acid A2251-((2,5-dichlorothiophen-3-yl)methyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2262-(5-chloropyridin-3-yl)-1-((2,5-dichlorothiophen-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2271-((2,5-dichlorothiophen-3-yl)methyl)-4-methyl-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A2281-((2,4-dichlorothiophen-5-yl)methyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2292-(5-chloropyridin-3-yl)-1-((2,4-dichlorothiophen-5-yl)methyl)-4-methyl-1H-imidazole-5-carboxylic acid A2301-((2,4-dichlorothiophen-5-yl)methyl)-4-methyl-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A2311-(2-chloro-5-methylbenzyl)-4-methyl-2-(5-methylpyridin-3-yl)-1H-imidazole-5-carboxylic acid A2321-(2-chloro-5-methylbenzyl)-2-(5-chloropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2331-(benzo[b]thiophen-7-ylmethyl)-2-(5-chloropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2341-(benzo[b]thiophen-7-ylmethyl)-2-(5-fluoropyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2351-(benzo[b]thiophen-7-ylmethyl)-2-(5-chloropyridin-3-yl)-4-isopropyl-1H-imidazole-5-carboxylic acid A2361-(benzo[b]thiophen-7-ylmethyl)-2-(5-chloropyridin-3-yl)-4-cyclopropyl-1H-imidazole-5-carboxylic acid A2373-chloro-5-(1-(2,5-dichlorobenzyl)-5-(1H-tetrazol-5-yl)-1H-imidazol-2-yl)pyridine A2381-(2,5-dimethylbenzyl)-4-methyl-2-(pyridin-4-yl)-1H-imidazole-5-carboxylic acid A2402-(6-methoxypyridin-2-yl)-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylic acid A2441-(2,5-dichlorobenzyl)-4-methyl-2-(pyridin-4-yl)-1H-imidazole-5-carboxylic acid A2451-(2,5-dichlorobenzyl)-4-methyl-2-(pyridin-2-yl)-1H-imidazole-5-carboxylic acid A2461-(2,5-dichlorobenzyl)-2-(6-methoxypyridin-2-yl)-4-methyl-1H-imidazole-5-carboxylic acid A2471-(2,5-dichlorobenzyl)-4-methyl-2-(pyridin-2-yloxy)-1H-imidazole-5-carboxylic acid

TABLE 10 A2481-(2,5-dichlorobenzyl)-4-methyl-2-(pyridin-3-yloxy)-1H-imidazole-5-carboxylic acid A2502-((5-chloropyridin-3-yl)oxy)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A2512-((5-bromopyridin-3-yl)oxy)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A2521-(2,5-dichlorobenzyl)-4-methyl-2-((2-methylpyridin-3-yl)oxy)-1H-imidazole-5-carboxylic acid A2532-((2-chloropyridin-3-yl)oxy)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A2542-((2-bromopyridin-3-yl)oxy)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A2551-(2,5-dichlorobenzyl)-4-methyl-2-((5-methylpyridin-3-yl)oxy)-1H-imidazole-5-carboxylic acid A2561-(2,5-dichlorobenzyl)-4-methyl-2-((4-methylpyridin-3-yl)oxy)-1H-imidazole-5-carboxylic acid A2572-((4-chloropyridin-3-yl)oxy)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A2582-((4-bromopyridin-3-yl)oxy)-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylic acid A2622-((2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazol-5-yl)thio)-2-methylpropanoic acid A2631-((2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazol-5-yl)thio)cyclobutanecarboxylic acid A2662-((5-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazol-2-yl)thio)-2-methylpropanoic acid B11-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acidB2 1-((4-methylnaphthalen-1-yl)methyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B31-((4-bromobenzo[b]thiophen-3-yl)methyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B41-((2-methylnaphthalen-1-yl)methyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B61-((8-bromonaphthalen-1-yl)methyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B71-((4-methylbenzo[b]thiophen-3-yl)methyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B81-(benzo[b]thiophen-3-ylmethyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B92-(pyridin-3-yl)-1-((4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl)-1H-pyrrole-5-carboxylic acid

TABLE 11 Compound No. Compound Name B101-((4-chlorobenzo[b]thiophen-3-yl)methyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B111-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B121-(2,5-dimethylbenzyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B131-(2,5-dichlorobenzyl)-2-(5-methylpyridin-3-yl)-1H-pyrrole-5-carboxylicacid B141-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-1H-pyrrole-5-carboxylicacid B151-((4-chlorobenzo[b]thiophen-3-yl)methyl)-2-(5-methylpyridin-3-yl)-1H-pyrrole-5-carboxylic acid B161-((4-chlorobenzo[b]thiophen-3-yl)methyl)-2-(5-fluoropyridin-3-yl)-1H-pyrrole-5-carboxylic acid B172-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-pyrrole-5-carboxylicacid B181-((4-chlorobenzo[b]thiophen-3-yl)methyl)-2-(5-chloropyridin-3-yl)-1H-pyrrole-5-carboxylic acid B192-(pyridin-3-yl)-1-(quinolin-8-ylmethyl)-1H-pyrrole-5-carboxylic acidB20 1-(benzo[b]thiophen-7-ylmethyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid B211-(benzo[b]thiophen-7-ylmethyl)-2-(5-methylpyridin-3-yl)-1H-pyrrole-5-carboxylic acid B221-(benzo[b]thiophen-7-ylmethyl)-2-(5-fluoropyridin-3-yl)-1H-pyrrole-5-carboxylic acid B231-(benzo[b]thiophen-7-ylmethyl)-2-(5-chloropyridin-3-yl)-1H-pyrrole-5-carboxylic acid B24N-(methylsulfonyl)-1-(naphthalen-1-ylmethyl)-2-(pyridin-3 -yl)-1H-pyrrole-5-carboxamide B25N-(cyclopropylsulfonyl)-1-(naphthalen-1-ylmethyl)-2-(pyridin-3 -yl)-1H-pyrrole-5-carboxamide B261-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-N-(methylsulfonyl)-1H-pyrrole-5-carboxamide B27N-(cyclopropylsulfonyl)-1-(2,5-dichlorobenzyl)-2-(5-fluoropyridin-3-yl)-1H-pyrrole-5-carboxamide B281-(2,5-dichlorobenzyl)-N-(methylsulfonyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxamide B292-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-N-(methylsulfonyl)-1H-pyrrole-5-carboxamide

TABLE 12 Compound No. Compound Name B302-(5-chloropyridin-3-yl)-N-(cyclopropylsulfonyl)-1-(2,5-dichlorobenzyl)-1H-pyrrole-5-carboxamide B31N-(cyclopropylsulfonyl)-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxamide B32N-(cyclopropylsulfonyl)-1-(2,5-dichlorobenzyl)-2-(5-methylpyridin-3-yl)-1H-pyrrole-5-carboxamide B33(E)-3-(1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)- 1H-pyrrole-5-yl)acrylic acid B34 (E)-3-(1-(2,5-dichlorobenzyl)-2-(5-methylpyridin-3-yl)-1H-pyrrol-5-yl) acrylic acid B35(E)-3-(1-(2,5-dichlorobenzyl)-2-(5-fluoropyridin- 3-yl)-1H-pyrrol-5-yl)acrylic acid

More preferred are the compounds of A1, A2, A7, A13, A14, A15, A18, A19,A25, A26, A37, A38, A39, A43, A45, A71, A78, A81, A85, A86, A88, A89,A90, A91, A92, A93, A96, A98, A99, A100, A101, A104, A105, A108, A119,A121, A134, A135, A136, A137, A139, A140, A142, A143, A144, A145, A146,A147, A149, A150, A151, A154, A155, A156, A157, A166, A167, A168, A169,A171, A173, A174, A176, A177, A179, A180, A181, A182, A183, A185, A188,A191, A193, A194, A195, A196, A197, A200, A202, A204, A205, A206, A207,A208, A209, A210, A211, A212, A213, A214, A215, A216, A217, A218, A219,A220, A221, A225, A226, A227, A231, A232, A233, A235, A236, A237, A245,A248, A250, A251, A252, A253, A254, A255, A256, A257, A258, B1, B2, B3,B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, B20, B21,B22, B23, B24, B25, B26, B27, B28, B29, B30, B31, B32, B33, B34, andB35. Even more preferred are A1, A2, A7, A13, A14, A15, A19, A26, A81,A119, A121, A134, A135, A137, A139, A147, A156, A169, A233, B1, and B11.

The pyridine derivative represented by the above formula (I) can beconverted into its prodrugs by conventional means. A prodrug refers to acompound that is converted into a pyridine derivative represented by theformula (I) in the body by enzymes, gastric acids, etc. Prodrugs for thepyridine derivative represented by the formula (I) include compounds inwhich the carboxyl group in the pyridine derivative has been esterifiedor amidated (such as those in which the carboxyl group has been C₁₋₆alkyl esterified, phenyl esterified, carboxymethyl esterified,dimethylaminomethyl esterified, pivaloyloxymethyl esterified,ethoxycarbonyloxyethyl esterified, phthalidyl esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified,cyclohexyloxycarbonylethyl esterified, or methylamidated), compounds inwhich the hydroxyl group in the pyridine derivative has been acylated,alkylated, phosphorylated, or borated (such as those in which thehydroxyl group has been acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated,dimethylaminomethylcarbonylated, or tetrahydropyranylated), or compoundsin which the amino group in the pyridine derivative has been acylated,alkylated, or phosphorylated (such as those in which the amino group hasbeen eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, tetrahydropyranylated, pyrrolidylmethylated,pivaloyloxymethylated, or tert-butylated). In addition, prodrugs for thepyridine derivative represented by the formula (I) may be compoundswhich are converted into a pyridine derivative represented by theformula (I) under physiological conditions, such as those described onpages 163 to 198 of “Iyakuhin no Kaihatsu [Development ofPharmaceuticals],” volume 7, Bunshi Sekkei [Molecular Design], publishedin 1990 by Hirokawa Shoten. Note that, among the pyridine derivativesrepresented by the formula (I), a compound in which R₃ and/or R₄ is—CO₂R₅ or a compound in which R₃ and R₄ are fused to form a lactone ringcan also be a prodrug which yields in the body a compound in which R₃and/or R₄ is a carboxylic acid or a compound in which R₃ is an alkylgroup substituted with a hydroxyl group and R₄ is a carboxyl group. Suchpyridine derivatives represented by the formula (I) that can also be aprodrug include A3, A221, A267, A268, A269, A270, A271, A272, A273,A274, A275, A276, A277, A278, A279, A280, A281, and A282.

If necessary, the pyridine derivative represented by formula (I), or aprodrug thereof, of the present invention can be converted into itspharmaceutically acceptable salts. Such salts include, for example,salts with inorganic acids, such as hydrochloric acid, hydrobromic acid,hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, andcarbonic acid; salts with organic acids, such as formic acid, aceticacid, propionic acid, trifluoroacetic acid, phthalic acid, oxalic acid,malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonicacid; salts with amino acids, such as lysine, arginine, ornithine,glutamic acid, and aspartic acid; salts with alkali metals, such assodium, potassium, and lithium; salts with alkaline-earth metals, suchas calcium and magnesium; salts with metals, such as aluminium, zinc,and iron; salts with organic bases, such as methylamine, ethylamine,diethylamine, trimethylamine, triethylamine, ethylenediamine,piperidine, piperazine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine,N-methyl glucamine, and N,N′-dibenzylethylenediamine; ammonium salts,and the like.

If necessary, the pyridine derivative represented by the above formula(I), or a prodrug thereof, or a pharmaceutically acceptable saltthereof, can be converted into its solvates. Such solvents can includewater, methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol,acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate,diethyl ether, t-butyl methyl ether, benzene, toluene, DMF, DMSO, etc.Particularly, water, methanol, ethanol, 1-propanol, 2-propanol,acetonitrile, acetone, methyl ethyl ketone, and ethyl acetate can bementioned as being preferred.

Although synthesis of the pyridine derivatives represented by the aboveformula (I) may be carried out by any method, the present derivativescan be synthesized as shown in Scheme A below when A is a single bond;R₁ is a nitrogen atom; R₃ is an alkyl group having 1 to 6 carbon atomsor a trifluoromethyl group; and R₄ is a carboxyl group, —CO₂R₅, or—CONHSO₂R₅. That is, after the imidazole derivative (IV) is brominatedto give the compound (V), N-alkylation is carried out by a reactionusing a base and a halide compound, or by a Mitsunobu reaction using analcohol, to give the compound (II-1). The compound (I-1) is obtained bya Suzuki coupling reaction of the compound (II-1) and a boronatederivative. The compound (I-2) can be obtained by hydrolyzing the estergroup. Furthermore, if necessary, the acylsulfonamide (I-3) can also beobtained by carrying out a condensation reaction with analkylsulfonamide.

Suitable reagents for the bromination of the compound (IV) to (V) inScheme A can include bromine, N-bromosuccinimide (NBS), etc. Solvents inthis reaction include, but are not particularly limited to, for example,ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane,or 1,2-diethoxyethane, halogenated solvents such as dichloromethane orcarbon tetrachloride, acetonitrile, mixed solvents thereof, or the like.This reaction proceeds at 0° C. to 100° C., but it is preferably carriedout at room temperature to 50° C.

The N-alkylation of the compound (V) to the compound (II-1) proceeds ina reaction using a base and a halide compound, or by a Mitsunobureaction using an alcohol. When a base and a halide compound are used,the base can include potassium carbonate, cesium carbonate,triethylamine, diisopropylethylamine, sodium hydride, etc., among whichthe preferred base is potassium carbonate, cesium carbonate,triethylamine, or diisopropylethylamine. The halide compound includeschloride, bromide, or iodide, among which the preferred halide compoundis a chloride or bromide. The temperature for the reaction in thepresence of a base and a halide compound is preferably from roomtemperature to 150° C., and more preferably from 50° C. to 120° C.Solvents in this reaction include, but are not particularly limited to,for example, ethers such as tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxyethane, or 1,2-diethoxyethane, amides such asdimethylformamide or N-methylpyrrolidone, dimethyl sulfoxide (DMSO),toluene, xylene, mixed solvents thereof, or the like. The N-alkylationof the compound (V) to the compound (II-1) also proceeds by a Mitsunobureaction with an alcohol. As for conditions for the Mitsunobu reaction,a phosphine compound, a condensation agent, an alcohol, and the compound(V) react in an inert solvent to give the compound (II-1). The phosphineincludes tributylphosphine, triphenylphosphine, tricyclohexylphosphine,etc., but preferably triphenylphosphine. A preferred condensation agentis diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate(DIAD). The reaction temperature for this Mitsunobu reaction may beanywhere from 0° C. to 100° C., but the preferred reaction temperatureis from room temperature to 80° C. The solvent in the Mitsunobu reactionincludes, but is not particularly limited to, for example, ethers suchas tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, or1,2-diethoxyethane, amides such as dimethylformamide orN-methylpyrrolidone, halogenated solvents such as dichloromethane,toluene, xylene, mixed solvents thereof, or the like.

The Suzuki coupling reaction of the compound (II-1) to the compound(I-1) proceeds by heating the compound (II-1), a boronate derivative, apalladium catalyst, and a base in a reaction-inert solvent. Preferably,this reaction is carried out under an inert gas atmosphere. Preferredexamples of the boronate derivative can include boronic acid and boronicacid pinacol ester. As the palladium catalyst,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(PdCl₂(dppf)), tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), or thelike is preferably used. As the base, potassium carbonate, cesiumcarbonate, or potassium phosphate can be mentioned as being preferred.Although the solvent in this reaction is not particularly limited, it ispreferable to use, for example, ethers such as tetrahydrofuran (THF),1,4-dioxane, 1,2-dimethoxyethane, or 1,2-diethoxyethane, amides such asdimethylformamide or N-methylpyrrolidone, alcohols such as ethanol,2-propanol, or butanol, toluene, xylene, water, or mixed solventsthereof. This reaction proceeds at 50° C. to 150° C., but it ispreferably carried out at 80° C. to 120° C.

The hydrolysis reaction of the compound (1-1) to the compound (1-2)proceeds by reacting the compound (I-1) with an equivalent or a slightexcess of a base in a mixed solvent of a reaction-inert solvent andwater. Preferred bases can include sodium hydroxide, potassiumhydroxide, or lithium hydroxide. Although the solvent is notparticularly limited, it is preferable to use, for example, a mixedsolvent of an organic solvent, such as tetrahydrofuran (THF) or alcohol(such as methanol or ethanol), and water for the reaction. This reactionproceeds at 0° C. to 100° C., but it is preferably carried out at roomtemperature to 60° C.

The condensation reaction of the compound (I-2) to the compound (I-3)proceeds by reacting the compound (I-2) with an alkylsulfonamide in thepresence of a base and a condensation agent in an inert solvent. Thesolvent includes, for example, ethers such as tetrahydrofuran (THF),1,4-dioxane, 1,2-dimethoxyethane, or 1,2-diethoxyethane, halogenatedsolvents such as dichloromethane or carbon tetrachloride, acetonitrile,mixed solvents thereof, or the like. The preferred solvent istetrahydrofuran (THF), dimethylformamide, or dichloromethane. The basecan include potassium carbonate, cesium carbonate, triethylamine,diisopropylethylamine, sodium hydride, etc., but the preferred base istriethylamine or diisopropylethylamine. The condensation agent includesdicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI orWSC), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU), etc., but preferably WSC. The reactiontemperature may be anywhere from 0° C. to 100° C., but the preferredreaction temperature is from room temperature to 50° C.

Note that the compound of the formula (II) discussed above can be usedas the compound (II-1) in Scheme A above.

The present derivatives can also be synthesized according to Scheme Bbelow, for example, when A is a single bond, R₁ is a nitrogen atom, R₃is an alkyl group having 1 to 6 carbon atoms, and R₄ is a carboxylgroup, —CO₂R₅, or —CONHSO₂R₅. That is, after the compound (VIII) isobtained by an imidazole ring-forming reaction using the compound (VI)and the compound (VII), N-alkylation is carried out by a reaction usinga base and a halide compound, or by a Mitsunobu reaction using analcohol, to give the compound (I-1). As in Scheme A, the compound (I-2)can be obtained by hydrolyzing the ester group. Furthermore, ifnecessary, the acylsulfonamide compound (I-3) can also be obtained bycarrying out condensation with an alkylsulfonamide.

Here, the imidazole ring-forming reaction using the compound (VI) andthe compound (VII) proceeds, for example, by heating the compound (VI)and the compound (VII) in a mixed solvent of toluene and water in thepresence of 2 or more equivalents, preferably 10 or more equivalents, ofammonium acetate. The reaction temperature for this reaction ispreferably from room temperature to 150° C., and more preferably from50° C. to 120° C. Preferably, the N-alkylation reaction of the compound(VIII) to the compound (I-1), the hydrolysis reaction of the compound(I-1) to the compound (I-2), and the condensation reaction of thecompound (I-2) to the compound (I-3) are carried out under theconditions described in Scheme A.

The present derivatives can be synthesized according to Scheme C belowwhen A is a single bond, R₁ is a nitrogen atom, R₃ is a hydrogen atom oran alkyl group having 1 to 6 carbon atoms, and R₄ is a carboxyl group or—CO₂R₅. That is, after the compound (III-1) is obtained by anN-alkylation reaction of the imidazole derivative (IV), the compound(II-1) is obtained by bromination. As in Scheme A, Suzuki coupling ofthe compound (II-1) and a boronate derivative is carried out to give thecompound (I-1). Furthermore, the compound (I-2) can be obtained byhydrolyzing the ester group. In addition, as an alternative route whenR₃ is a hydrogen atom, the compound (I-1) can also be obtained by anN-alkylation reaction of the easily synthesizable compound (IX) to givethe compound (X), followed by a bromination reaction to give thecompound (XI), and further followed by a CO-insertion reaction in analcohol using palladium.

For the N-alkylation reaction of the compound (IV) to the compound(III-1) in Scheme C, the conditions described in Scheme A are preferred.For the bromination of the compound (III-1) to the compound (II-1), theconditions described in Scheme A are preferred, and the conditions offurther adding a catalytic amount of 2,2′-azobis(isobutyronitrile)(AIBN) are more preferred. Preferably, the Suzuki coupling reaction ofthe compound (II-1) to the compound (I-1) and the subsequent hydrolysisreaction are carried out under the conditions described in Scheme A. TheN-alkylation reaction of the compound (IX) to the compound (X) and thebromination of the compound (X) to the compound (XI) are preferablycarried out under the conditions described in Scheme A. The CO-insertionreaction of the compound (XI) to the compound (I-1) proceeds by using apalladium catalyst, a base, and the compound (XI) in an alcohol solventunder a CO atmosphere. As the alcohol solvent, methanol or ethanol ispreferred. As the palladium catalyst,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(PdCl₂(dppf)), tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), etc.is preferred. The base is preferably triethylamine ordiisopropylethylamine. The reaction temperature for this reaction ispreferably from room temperature to 150° C., and more preferably from50° C. to 90° C.

Note that the compound of the formula (II) discussed above can be usedas the compound (II-1) in Scheme C above, and the compound of theformula (III) discussed above can be used as the compound (III-1) inScheme C above.

The present derivative can be synthesized according to Scheme D belowwhen A is a single bond, R₁ is a nitrogen atom, R₃ is a chlorine atom,and R₄ is a carboxyl group. That is, the amidine hydrochloride (XII) anddihydroxyacetone dimer are used to form an imidazole ring to obtain thealcohol compound (XIII). After the compound (XIV) is obtained bychlorination, the aldehyde compound (XV) is obtained by oxidation. Thecompound (I-4) can be obtained by N-alkylation to give the compound(XVI), followed by, further oxidation. In addition, as an alternativeroute, the compound (I-4) can also be obtained by chlorination of thecompound (I-5) which corresponds to the compound (I-1) in Scheme C abovewherein R₃ is a hydrogen atom to give the compound (I-6), followed byhydrolysis.

The imidazole ring-forming reaction of the compound (XII) to thecompound (XIII), is preferably carried out under the conditions whereammonium chloride and dihydroxyacetone dimer are used in aqueousammonia. This reaction proceeds at 50° C. to 100° C., but it ispreferably carried out at 80 to 100° C. Chlorinating agents for thecompound (XIII) can include N-chlorosuccinimide (NCS), chlorine, etc.,but preferably N-chlorosuccinimide (NCS). This reaction proceeds at roomtemperature to 50° C., but it is more preferable to perform the reactionat room temperature in order to reduce side reactions. The oxidation ofthe compound (XIV) to the compound (XV) is preferably carried out usingmanganese dioxide, and the reaction solvent is preferably a halogenatedsolvent such as dichloromethane. The N-alkylation of the compound (XV)to the compound (XVI) is preferably carried out under the conditionsdescribed in Scheme A. For the oxidation reaction of the compound (XVI)to the compound (I-4), the Pinnick reaction is widely known, and theconditions of using sodium chlorite and sodium dihydrogenphosphate inthe presence of 2-methyl-2-butene are preferred. As the reactionsolvent, it is preferable to use a mixed solvent of tetrahydrofuran(THF), or an alcohol such as t-butanol or propanol, and water. Thereaction temperature is preferably from room temperature to 50° C. Asfor the chlorination of the compound (I-5) to the compound (I-6), it ispreferable to perform the reaction using N-chlorosuccinimide (NCS) inacetonitrile. This reaction proceeds at room temperature to 100° C., butit is preferably carried out at 50° C. to 80° C. The hydrolysis of thecompound (I-6) to the compound (I-4) is preferably carried out under theconditions described in Scheme A.

The present derivatives can be synthesized according to Scheme E belowwhen A is a single bond, R₁ is a nitrogen atom, R₃ is an alkyl grouphaving 1 to 6 carbon atoms (which may optionally be substituted with oneor more of a hydroxyl group, an amino group, a dialkylamino group having1 to 6 carbon atoms which may optionally form a ring, an imidazole ring,a pyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholinering, and piperazine ring (which may optionally be substituted with oneor more of an alkyl group having 1 to 6 carbon atoms and analkylsulfonyl group having 1 to 6 carbon atoms)), an acetyl group, adifluoromethyl group, or an ethynyl group, and R₄ is a carboxyl group.That is, the diester compound (XVII) is converted into the compound(XVIII) by a bromination reaction and then into the compound (II-2) byan N-alkylation reaction. After the compound (I-7) is subsequentlyobtained by a Suzuki coupling reaction, the hydroxymethyl compound(I-8), reduced only at the 4-position, is obtained by a selectivereduction reaction using diisobutylaluminum hydride (DIBAL-H). Thecompound (I-2) can be synthesized by converting the hydroxymethyl moietyinto various R₃ moieties through various common conversion reactions inorganic synthesis, finally followed by a hydrolysis reaction.

In Scheme E, the bromination of the compound (XVII) to the compound(XVIII), the N-alkylation reaction of the compound (XVIII) to thecompound (II-2), and the Suzuki coupling reaction of the compound (II-2)to the compound (I-7) are preferably carried out under the conditionsdescribed in Scheme A. As for the reduction reaction of the compound(I-7) to the compound (I-8), it is preferable to carry out a reductionreaction in tetrahydrofuran (THF) solvent using diisobutylaluminumhydride (DIBAL-H). This reaction proceeds at −50° C. to 50° C., but itis preferably carried out at −40° C. to room temperature. As for theconversion of the hydroxymethyl moiety of the compound (I-8), furtherconversion into various R₃ moieties is made possible by converting thealcohol moiety into an aldehyde through oxidation with manganesedioxide, or by converting the alcohol moiety into a bromo group usingtribromophosphine, followed by further transformations of these aldehydeand bromo group into R₃ moieties. The hydrolysis is preferably carriedout under the conditions described in Scheme A.

Note that the compound of the formula (II) discussed above can be usedas the compound (II-2) in Scheme E above.

The present derivatives can be synthesized according to Scheme F belowwhen A is a single bond, R₁ is a nitrogen atom, R₃ is an iodine atom, aphenyl group, a pyridyl group, a phenoxy group, a cyano group, an alkoxygroup having 1 to 6 carbon atoms, or an alkenyl group having 2 to 6carbon atoms, and R₄ is a carboxyl group. That is, the compound (X)obtained in Scheme (C) is iodinated to give the compound (XIX), followedby selective formylation to give the compound (XX). After the compound(XXI) is subsequently obtained by Suzuki coupling, cyanation, oretherification through the introduction of alcohol, thiol, phenol, orthe like, etc. under the conditions of using palladium, the compound(I-2) can be obtained by carrying out the Pinnick oxidation. When R₃ isan iodine atom, the compound (XX) is directly oxidated to give thecompound (I-2).

Preferably, the iodination reaction of the compound (X) to the compound(XIX) in Scheme F is carried out in methanol using iodine and silversulfate. This reaction proceeds at 0° C. to 100° C., but it ispreferably carried out at room temperature to 50° C. As for theselective formylation of the compound (XIX) to the compound (XX), it ispreferable to perform the reaction using a Grignard reagent such asEtMgBr, or a lithium reagent such as nBuLi, in DMF, or in a mixedsolvent of tetrahydrofuran (THF) and DMF. This reaction proceeds at −50°C. to 50° C., but it is preferably carried out at 0° C. to roomtemperature. In the conversion of the compound (XX) to the compound(XXI), the Suzuki coupling reaction is preferably carried out under theconditions described in Scheme A. The cyanation using palladium, iscarried out preferably under the conditions where a palladium catalyst,such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)(PdCl₂ (dppf)) or tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), andZnCN₂ are heated in DMF. This reaction proceeds at 50° C. to 150° C.,but it is preferably carried out at 80° C. to 100° C. For theetherification through the introduction of alcohol, thiol, phenol, orthe like, the conditions of using CuI, 1,10-phenanthroline, and cesiumcarbonate in the presence of the compound (XX) and any of the alcohol,thiol, phenol, or the like in toluene solvent are preferred. Thereaction temperature is preferably from 50° C. to 100° C. The Pinnickoxidation reaction of the compound (XX) or the compound (XXI) ispreferably carried out under the conditions described in Scheme D.

The present derivatives can be synthesized according to Scheme G belowwhen A is a single bond, R₁ is a nitrogen atom, R₃ is a hydrogen atom,R₄ is a tetrazolyl group, acrylic acid, or thiomethylpropanoic acid.That is, for a tetrazole compound, the compound (I-9) can be obtained byintroducing a cyano group using palladium into the compound (XI)obtained in Scheme C above to give the compound (XXII) and thenconverting the cyano group into tetrazolyl group using sodium azide. Foracrylic acid, the compound (I-10) can be obtained by performing a Heckreaction on the compound (XI) to give the compound (XXIII), followed bya hydrolysis reaction. For thiomethylpropanoic acid, the compound (I-11)can be obtained by the introduction of a SH group using palladium togive the compound (XXIV), followed by S-alkylation to give the compound(XXV), and finally followed by hydrolysis.

For the cyanation reaction of the compound (XI) to the compound (XXII),the conditions of heating in DMF with a palladium catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (PdCl₂(dppf)) or tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), and ZnCN₂are preferred. This reaction proceeds at 50° C. to 150° C., but it ispreferably carried out at 80° C. to 100° C. The conversion of thecompound (XXII) to the compound (I-9), is carried out preferably byusing triethylamine hydrochloride and sodium azide in DMF. This reactionproceeds at 100° C. to 170° C., but it is preferably carried out at 120°C. to 150° C. The Heck reaction for converting the compound (XI) to thecompound (XXIII) proceeds by using a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (PdCl₂(dppf)) or tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), a basesuch as potassium carbonate, potassium acetate, triethylamine, ordiisopropylethylamine, the compound (XI), and an acrylic acid ester inacetonitrile, or in an amide type solvent such as DMF or DMA, underheated conditions. This reaction proceeds at room temperature to 150°C., but it is preferably carried out at 80° C. to 140° C. The hydrolysisis preferably carried out under the conditions described in Scheme A. Asfor the introduction of a SH group into the compound (XI) to give thecompound (XXIV), an alkylthiol moiety is introduced by heating thecompound (XI), 2-ethylhexyl 3-mercaptopropionate, Pd₂(dba)₃, Xantphos,and diisopropylethylamine in 1,4-dioxane under a nitrogen atmosphere,and then a β-elimination reaction is carried out under basic conditionsto give the compound (XXIV), with reference to the document: Org. Lett.2004, 6, 4587-4590; or Org. Lett. 2007, 9, 3687-3689. For theβ-elimination reaction, the conditions of using a slight excess of KOtBuin DMF at room temperature are preferred. The S-alkylation of thecompound (XXIV) to the compound (XXV) is preferably carried out underconditions similar to those for the N-alkylation in Scheme A, and morepreferably under the conditions of using a base and a halide compound.The hydrolysis is preferably carried out under the conditions describedin Scheme A.

The present derivatives can be synthesized according to Scheme H belowwhen A is an oxygen atom, R₁ is a nitrogen atom, R₃ is an alkyl grouphaving 1 to 6 carbon atoms, and R₄ is a carboxyl group. That is, thecompound (I-13) can be synthesized by performing a substitution reactionusing a phenol and a base on the compound (II-1) obtained in Scheme Aabove to give the compound (I-12), and then performing a hydrolysisreaction.

The substitution reaction of the compound (II-1) to the compound (I-12)proceeds by reacting compound (II-1) with a phenol in DMF, in thepresence of a base, such as potassium carbonate or cesium carbonate.This reaction proceeds at 50° C. to 150° C., but it is preferablycarried out at 90° C. to 130° C. The hydrolysis of the compound (I-12)to the compound (I-13) is preferably carried out under the conditionsdescribed in Scheme A.

Note that the compound of the formula (II) discussed above can be usedas the compound (II-1) in Scheme H above.

Furthermore, the present derivatives can be synthesized according toScheme I below when A is a single bond, R₁ is CH, R₃ is a hydrogen atom,and R₄ is a carboxyl group or acrylic acid. That is, for a carboxylicacid, after the known pyrrole derivative (XXVI) is N-alkylated to givethe compound (II-3), the compound (XXVII) is obtained by a Suzukicoupling reaction with a boronate derivative. The target compound (I-14)can be obtained by a subsequent oxidation reaction. For an acrylic acid,the compound (I-15) can be obtained by performing a Horner-Emmonsreaction on the compound (XXVII) to give the compound (XXVIII), followedby hydrolysis.

Preferably, the N-alkylation reaction of the compound (XXVI) to thecompound (II-3) in Scheme I and the subsequent Suzuki coupling reactionof the compound (II-3) are carried out under the conditions described inScheme A. Preferably, the oxidation reaction of the compound (XXVII) iscarried out under the conditions described in Scheme D. TheHorner-Emmons reaction of the compound (XXVII) to the compound (XXVIII)proceeds by reacting the compound (XXVII) with ethyldiethylphosphonoacetate in THF, in the presence of a base, such assodium hydride or nBuLi. The reaction temperature is preferably from 0°C. to room temperature. The subsequent hydrolysis is preferably carriedout under the conditions described in Scheme A.

Note that the compound of the formula (II) discussed above can be usedas the compound (II-3) in Scheme I above.

An agent for treatment or prevention of gout, hyperuricemia, and thelike, containing a pyridine derivative or a prodrug thereof, or apharmaceutically acceptable salt thereof, or a solvate thereof, of thepresent invention as an active ingredient is prepared with carriers,excipients, and other additives commonly used to formulatepharmaceutical preparations. The carriers and excipients to formulatepharmaceutical preparations may be either solid or liquid and include,for example, lactose, magnesium stearate, starch, talc, gelatin, agar,pectin, Arabian gum, olive oil, sesame oil, cocoa butter, ethyleneglycol, etc., and others that are commonly used. Administration may bein any form of oral administration such as via tablets, pills, capsules,granules, powders, or liquid preparations, or of parenteraladministration such as via injections, such as intravenous injection andintramuscular injection, suppositories, or transdermal administration.

For the purpose of the present invention, “preventing” refers toobviating contraction or development of a disease in an individual whohas not yet contracted or developed it, and “treating” refers to curing,suppressing, or ameliorating a disease or symptom in an individual whohas already contracted or developed it.

The effective dose of the active ingredient in a URAT1-inhibitor or anagent for treatment or prevention of the present invention may varydepending upon the route of administration, the age and sex of thepatient, the extent of the disease, and the like, but it is generallyabout 0.1 to 100 mg/day. The dose frequency is generally 1 to 3times/day or 1 to 7 times/week. It is preferred that pharmaceuticalpreparations be prepared to meet these conditions.

EXAMPLES

Hereinafter, the present invention will be described in greater detailby way of working examples, without being limited thereto. Abbreviationsin the present invention are as follows:

-   DMF=N,N-dimethylformamide-   THF=tetrahydrofuran-   NBS=N-bromosuccinimide-   NCS=N-chlorosuccinimide-   DEAD=diethyl azodicarboxylate-   DIAD=diisopropyl azodicarboxylate-   PdCl₂    (dppf)=[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   PdCl₂    (dppf).CH₂Cl₂=[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)    dichloromethane complex-   BSA=N,O-bis(trimethylsilyl)acetamide-   AIBN=2,2′-azobis(isobutyronitrile)-   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   WSC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   DMAP=N,N-dimethylamino-4-aminopyridine-   DIBAL-H=diisobutylaluminum hydride-   DAST=diethylaminosulfur trifluoride

The structures of the isolated, novel compounds were confirmed by ¹H-NMRand/or mass spectrometry using single quadrupole instrumentationequipped with an electrospray source, and other appropriate analyticalmethods.

For the compounds whose ¹H-NMR spectra (400 MHz, DMSO-d₆, CDCl₃, orCD₃OD) were measured, their chemical shifts (δ: ppm) and couplingconstants (J: Hz) are shown. For the mass spectroscopy results, theobserved measurement is shown as M⁺+H, i.e., the value of compound'smolecular mass (M) plus a proton (H+). Abbreviations below referrespectively to the following.

s=singlet, d=doublet, t=triplet, q=quartet, brs=broad singlet,m=multiplet.

The compounds synthesized according to the methods of the followingExamples were also analyzed by high-performance liquid chromatography(HPLC) analysis and by mass spectroscopy using a time-of-flight massspectrometer (TOF-MS: Time of Flight-Mass Spectroscopy) equipped with anelectrospray ion source.

The retention time (in minutes) of a compound in the HPLC analysis underthe following analytical conditions is shown as HPLC retention time.

HPLC Measurement Conditions Instrument: Hewlett-Packard 1100HPLC

Column: Imtakt Cadenza CD-C18 100 mm×4.6 mm 3 μmUV: PDA detection (254 nm)Column temperature: 40° C.

Gradient Conditions: Solvents:

A: H₂O/acetonitrile=95/5

-   -   0.05% TFA (trifluoroacetic acid)

B: H₂O/acetonitrile=5/95

-   -   0.05% TFA (trifluoroacetic acid)        Flow rate: 1.0 mL/min

Gradients:

-   -   0 to 1 minute, Solvent B: 2%, Solvent A: 98%    -   1 to 14 minutes, Solvent B: 2%→100%, Solvent A: 98%→0%    -   14 to 17 minutes, Solvent B: 100%, Solvent A: 0%    -   17 to 19 minutes, Solvent B: 100%→2%, Solvent A: 0%→98%

For the mass spectroscopy results, the value of “M⁺+H” observed usingthe apparatus and analytical conditions listed below (Obs. Mass: i.e.,the observed value of compound's molecular mass (M) plus a proton (H⁺))and the calculated value of “M⁺+H” (Pred. Mass), as well as thecompositional formula calculated from the observed value of “M⁺+H,” areshown.

TOF-MS measurement conditionsMass spectrometer: Shimadzu Corporation LCMS-IT-TOF

LC: Prominence

Column: Phenomenex Synergi Hydro-RP 4.0 mm×20 mm 2.5 μmUV: PDA detection (254 nm)Flow rate: 0.6 mL/minColumn temperature: 40° C.Detection voltage: 1.63 kV

Gradient Conditions: Solvents:

A: H₂O/acetonitrile=95/5

-   -   0.1% HCO₂H

B: H₂O/acetonitrile=5/95

-   -   0.1% HCO₂H        Flow rate: 0.5 mL/min

Gradients:

-   -   0 to 0.2 minutes, Solvent B: 2%, Solvent A: 98%    -   0.2 to 2.5 minutes, Solvent B: 2%→100%, Solvent A: 98%→0%    -   2.5 to 3.8 minutes, Solvent B: 100%, Solvent A: 0%    -   3.8 to 4.0 minutes, Solvent B: 100%→2%, Solvent A: 0%→98%    -   4.0 to 5.0 minutes, Solvent B: 2%, Solvent A: 98%

Example 1 Production of4-methyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A2) (Scheme A)

(1) Ethyl 4-methyl-1H-imidazole-5-carboxylate (7.5 g, 48.7 mmol) wasdissolved in acetonitrile (120 mL), N-bromosuccinimide (10.4 g, 58.4mmol) was added thereto, and then the mixture was stirred at roomtemperature for 3 hours. After the reaction, saturated aqueous sodiumhydrogen carbonate was added and the mixture was extracted twice withethyl acetate. After washing with saturated aqueous sodium chloride, theorganic layer was dried over anhydrous sodium sulfate. Afterconcentrating the organic layer, the residue was purified by columnchromatography to obtain ethyl2-bromo-4-methyl-1H-imidazole-5-carboxylate (3.6 g):

¹H-NMR (CDCl₃) δ: 4.35 (2H, q, J=7.1 Hz), 2.51 (3H, s), 1.37 (3H, t,J=7.1 Hz);

ESI-MS m/z=233 (M⁺+H).

(2) Ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (5 g, 21.45 mmol)was dissolved in DMF (40 mL), potassium carbonate (5.93 g, 42.9 mmol)and 1-(chloromethyl)naphthalene (4.56 g, 25.8 mmol) were added thereto,and the mixture was stirred at 80° C. for 2 hours. After the reaction,water was added and the mixture was extracted twice with ethyl acetate.The organic layer was washed with saturated aqueous sodium chloride anddried over anhydrous sodium sulfate. After concentrating the organiclayer, the residue was purified by column chromatography to obtain ethyl2-bromo-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylate(3.25 g):

¹H-NMR (CDCl₃) δ: 8.01 (1H, d, J=8.3 Hz), 7.91 (1H, d, J=7.8 Hz), 7.77(1H, d, J 8.3 Hz), 7.63-7.53 (2H, m), 7.33 (1H, t, J=7.6 Hz), 6.43 (1H,dd, J=7.3, 1.0 Hz), 6.07 (2H, s), 4.13 (2H, q, J=7.1 Hz), 2.58 (3H, s),1.11 (3H, t, J=7.1 Hz);

ESI-MS m/z=373 (M⁺+H).

(3) Ethyl2-bromo-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylate(1.5 g, 4.0 mmol), pyridin-3-ylboronic acid (0.74 g, 6.0 mmol), cesiumcarbonate (2.62 g, 8.0 mmol), and PdCl₂ (dppf) (0.3 g, 0.4 mmol) weredissolved in a mixed solvent of dioxane (15 mL) and water (3 mL), andthe solution was heated and stirred at 100° C. for 6 hours under anitrogen atmosphere. After cooling, the reaction mixture wasconcentrated under reduced pressure, ethyl acetate was added to theresidue, and the solution was washed with water and saturated aqueoussodium chloride. The organic layer was dried over anhydrous sodiumsulfate and subsequently concentrated under vacuum. The residue obtainedwas purified by column chromatography to obtain ethyl4-methyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A3, 1.46 g):

¹H-NMR (CDCl₃) δ: 8.78 (1H, d, J=2.0 Hz), 8.58 (1H, dd, J=4.9, 1.5 Hz),7.93-7.85 (2H, m), 7.82-7.77 (2H, m), 7.57-7.53 (2H, m), 7.38 (1H, t,J=7.6 Hz), 7.24-7.20 (1H, m), 6.73 (1H, d, J=6.3 Hz), 6.03 (2H, s), 4.13(2H, q, J=7.2 Hz), 2.67 (3H, s), 1.07 (3H, t, J=7.1 Hz);

ESI-MS m/z=372 (M⁺+H).

(4) Ethyl4-methyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl-1H-imidazole-5-carboxylate(1.46 g, 3.93 mmol) was dissolved in a mixed solvent of THF (10 mL) andmethanol (10 mL), and 2 M aqueous sodium hydroxide (4 mL, 8.0 mmol) wasadded to the solution, and then the mixture was heated and stirred at50° C. for 1 hour. After cooling to room temperature, 2 M hydrochloricacid (4 ml, 8.0 mmol) was added and the mixture was concentrated underreduced pressure. The residue was purified according to the conventionalmethod to obtain4-methyl-1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A2, 0.88 g):

¹H-NMR (DMSO-D₆) δ: 8.69 (1H, d, J=2.0 Hz), 8.60 (1H, dd, J=4.9, 1.5Hz), 8.05-8.01 (1H, m), 7.99-7.95 (1H, m), 7.93 (1H, dt, J=8.0, 2.0 Hz),7.84 (1H, d, J=8.3 Hz), 7.60-7.57 (2H, m), 7.46-7.40 (2H, m), 6.59 (1H,d, J=7.3 Hz), 6.09 (2H, s), 2.56 (3H, s);

HPLC retention time=7.40 min;

Pred. Mass=344.1394 (M⁺+H, C₂₁H₁₇N₃O₂);

Obs. Mass=344.1391 (M⁺+H).

Example 2 Production of1-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A7) (Scheme A)

(1) Ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (1.52 g, 6.0mmol), (4-chlorobenzo[b]thiophen-3-yl)methanol (1.79 g, 9.0 mmol)obtained according to a method described in a literature (for example,WO 2002/066457), and triphenylphosphine (2.36 g, 9.0 mmol) weredissolved in THF (15 mL), a 1.9 M solution of DIAD in toluene (4.73 mL,9.0 mmol) was added dropwise thereto under cooling at 0° C., and themixture was stirred at 30° C. for 10 hours. The solvent was distilledaway and the residue was purified by column chromatography to obtainethyl2-bromo-1-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-1H-imidazole-5-carboxylate(1.73 g):

¹H-NMR (CDCl₃) δ: 7.72 (1H, d, J=8.3 Hz), 7.41-7.24 (3H, m), 6.15 (2H,s), 4.21 (2H, q, J=7.1 Hz), 2.57 (3H, s), 1.20 (3H, t, J=7.1 Hz);

ESI-MS m/z=413 (M⁺+H).

(2) Ethyl2-bromo-1-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-1H-imidazole-5-carboxylate(800 mg, 1.93 mmol), pyridin-3-ylboronic acid (366 mg, 3.0 mmol), cesiumcarbonate (1.06 g, 3.0 mmol), PdCl₂ (dppf).CH₂Cl₂ (245 mg, 0.3 mmol)were dissolved in a mixed solvent of dioxane (19 mL) and water (1 mL),and the solution was heated and stirred at 100° C. for 5 hours under anitrogen atmosphere. After cooling, ethyl acetate was added to extractthe reaction mixture, the organic layer was washed with saturatedaqueous sodium chloride, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue obtained was purifiedby column chromatography to obtain ethyl1-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A267, 0.63 g):

ESI-MS m/z=412 (M⁺+H).

(3) Ethyl1-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(0.63 g, 1.53 mmol) was dissolved in a mixed solvent of THF (6 mL),methanol (6 mL), and water (3 mL), 1 M aqueous sodium hydroxide (3 mL,3.0 mmol) was added to the solution, and the mixture was stirred at 60°C. for 3 hours. After cooling, the reaction mixture was neutralized bythe addition of 1 M hydrochloric acid (3 mL, 3.0 mmol) and the organicsolvent was distilled away. The residue was extracted with ethyl acetateand the organic layer was washed with saturated aqueous sodium chloride.After being dried over anhydrous magnesium sulfate, the organic layerwas concentrated under reduced pressure. The residue was purified by aconventional method to obtain1-((4-chlorobenzo[b]thiophen-3-yl)methyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A7, 0.26 g):

¹H-NMR (DMSO-D₆) δ: 8.72 (1H, d, J=2.0 Hz), 8.60 (1H, dd, J=4.9, 2.0Hz), 7.99-7.93 (2H, m), 7.47-7.44 (2H, m), 7.37 (1H, t, J=8.0 Hz), 6.87(1H, s), 6.05 (2H, s), 2.60 (3H, s);

HPLC retention time=7.76 min:

Pred. Mass=384.0568 (M⁺+H, C₁₉H₁₄ClN₃O₂S);

Obs. Mass=384.0564 (M⁺+H).

Example 3 Production of4-chloro-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A9) (Scheme D)

(1) 3-Amidinopyridine hydrochloride (10 g, 63.5 mmol), dihydroxyacetonedimer (11.43 g, 63.6 mmol) and ammonium chloride (17 g, 317 mmol) weredissolved in 28% aqueous ammonia (100 mL), and the solution was stirredat 80° C. for 2 hours. After the reaction, saturated aqueous sodiumchloride (50 mL) was added and the aqueous layer was extracted threetimes with a mixed solvent of ethyl acetate and THF. The organic layerwas dried over anhydrous sodium sulfate and concentrated to obtain acrude product, which was subsequently washed with acetonitrile andhexane to obtain (2-(pyridin-3-yl)-1H-imidazol-5-yl)methanol (3 g):

ESI-MS m/z=176 (M⁺+H).

(2) In a mixed solvent of ethanol (30 mL) and 1,4-dioxane (30 mL) wasdissolved (2-(pyridin-3-yl)-1H-imidazol-5-yl)methanol (2.1 g, 12 mmol),N-chlorosuccinimide (1.6 g, 12 mmol) was added thereto, and the mixturewas stirred at room temperature for 48 hours. After the reaction, water(50 mL) and saturated aqueous sodium chloride (50 mL) were added and themixture was extracted twice with a mixed solvent of ethyl acetate andTHF. After being dried over anhydrous sodium sulfate, the organic layerwas concentrated and the residue was purified by column chromatographyto obtain (4-chloro-2-(pyridin-3-yl)-1H-imidazol-5-yl)methanol (600 mg):

¹H-NMR (DMSO-d₆) δ: 13.16 (1H, s), 9.09 (1H, d, J=2.0 Hz), 8.54 (1H, dd,J=4.9, 1.5 Hz), 8.24 (1H, dt, J=8.1, 2.0 Hz), 7.47 (1H, dd, J=7.8, 4.9Hz), 5.31 (1H, t, J=5.1 Hz), 4.45 (2H, d, J=4.9 Hz);

ESI-MS m/z=210 (M⁺+H).

(3) In dichloromethane (7 mL) was suspended(4-chloro-2-(pyridin-3-yl)-1H-imidazol-5-yl)methanol (600 mg, 2.86mmol), manganese dioxide (4 g, 46 mmol) was added thereto, and themixture was stirred at room temperature for 20 hours. After thereaction, the reaction mixture was filtered using celite andsubsequently the filtrate was concentrated to obtain4-chloro-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde (460 mg). Thismaterial was used as is for the next reaction without furtherpurification:

¹H-NMR (DMSO-d₆) δ: 14.22 (1H, s), 9.72 (1H, s), 9.24 (1H, s), 8.66 (1H,d, J=4.4 Hz), 8.42 (1H, d, J=7.3 Hz), 7.54 (1H, dd, J=7.8, 4.9 Hz);ESI-MS m/z=208 (M⁺+H).

(4) In DMF (1 mL) was dissolved4-chloro-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde (50 mg, 0.241mmol), potassium carbonate (66.6 mg, 0.482 mmol) and1-(chloromethyl)naphthalene (51.0 mg, 0.289 mmol) were added to thesolution, and the mixture was heated and stirred at 80° C. for 5 hours.After the reaction, water (5 mL) was added and the mixture was extractedtwice with ethyl acetate (5 mL). After being washed with saturatedaqueous sodium chloride, the organic layer was dried over anhydroussodium sulfate and subsequently concentrated to obtain4-chloro-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde(100 mg). This material was used as is for the next reaction withoutfurther purification:

ESI-MS m/z=348 (M⁺+H).

(5)4-Chloro-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazol-5-carbaldehyde(100 mg) and 2-methyl-2-butene (141 mg, 2 mmol) were dissolved in amixed solvent of THF (1 mL) and t-butanol (1 mL), an aqueous solution (2mL) of sodium chlorite (221 mg, 2.44 mmol) and sodium dihydrogenphosphate (292 mg, 1.87 mmol) was added dropwise thereto, and themixture was stirred at room temperature for 6 hours. After the reaction,water (5 mL) was added and the mixture was extracted twice with ethylacetate (5 mL). After being washed with saturated aqueous sodiumchloride, the organic layer was dried over sodium sulfate. Afterconcentrating the organic layer, the residue was purified by HPLC toobtain4-chloro-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A9, 2.53 mg):

HPLC retention time=8.52 min;

Pred. Mass=364.0847 (M⁺+H, C₂₀H₁₄ClN₃O₂);

Obs. Mass=364.0847 (M⁺+H).

Example 4 Production of4-cyclopropyl-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A11) (Scheme B)

(1) Ethyl 2-(triphenylphosphoranylidene)acetate (16.3 g, 47 mmol) wasdissolved in dichloromethane (160 mL), cyclopropanecarbonyl chloride(5.4 g, 51 mmol) and N,O-bis(trimethylsilyl)acetamide (BSA) (11.9 g, 58mmol) were added thereto under ice cooling, and the mixture was stirredat room temperature for 3 hours. After the reaction, water (100 mL) wasadded and the aqueous layer was extracted twice with dichloromethane.After being washed with saturated aqueous sodium chloride, the organiclayer was dried over anhydrous magnesium sulfate and was concentrated toobtain ethyl3-cyclopropyl-3-oxo-2-(triphenylphosphoranylidene)propanoate (19.0 g):

¹H-NMR (CDCl₃) δ: 7.67-7.40 (15H, m), 3.74 (2H, q, J=7.2 Hz), 3.35-3.33(1H, m), 0.85-0.81 (2H, m), 0.71-0.67 (2H, m), 0.65 (3H, t, J=7.3 Hz);

ESI-MS m/z=417 (M⁺+H).

(2) Ethyl 3-cyclopropyl-3-oxo-2-(triphenylphosphoranylidene)propanoate(19.0 g, 47 mmol) was dissolved in a mixed solvent of tetrahydrofuran(300 mL) and water (200 mL), oxone (34.7 g, 56 mmol) was added theretounder ice cooling, and the mixture was stirred at room temperature for 4hours. After the reaction, insoluble matter was removed by filtrationand the solid was washed with ethyl acetate. The filtrate wasconcentrated and the solvent was distilled away. The aqueous layer wasextracted twice with ethyl acetate (100 mL). After being washed withsaturated aqueous sodium chloride, the organic layer was dried overanhydrous magnesium sulfate. The residue obtained by concentrating theorganic layer was purified by column chromatography to obtain ethyl3-cyclopropyl-2,3-dioxopropanoate (7.47 g):

¹H-NMR (CDCl₃) δ: 4.34 (2H, q, J=7.1 Hz), 2.16-2.11 (1H, m), 1.31 (3H,t, J=7.1 Hz), 1.25-1.22 (2H, m), 1.15-1.10 (2H, m).

(3) Ethyl 3-cyclopropyl-2,3-dioxopropanoate (500 mg, 2.9 mmol), nicotinealdehyde (315 mg, 2.9 mmol), and ammonium acetate (2.26 g, 29 mmol) weredissolved in a mixed solvent of toluene (4 mL) and water (2 mL), and themixture was heated and stirred at 70° C. for 3 hours. After thereaction, the residue obtained by distilling away toluene was purifiedby a conventional method to obtain ethyl4-cyclopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate (416 mg):

¹H-NMR (DMSO-d₆) δ: 13.07 (1H, brs), 9.16 (1H, brs), 8.56 (1H, d, J=4.9Hz), 8.33 (1H, brs), 7.46 (1H, dd, J=7.8, 4.9 Hz), 4.30 (2H, brs), 2.59(1H, brs), 1.32 (3H, t, J=7.1 Hz), 0.97 (4H, brs);

ESI-MS m/z=258 (M⁺+H).

(4) Ethyl 4-cyclopropyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate (50mg, 0.194 mmol) was dissolved in DMF (1 mL), potassium carbonate (53.7mg, 0.389 mmol) and 1-(chloromethyl)naphthalene (41.2 mg, 0.233 mmol)were added to the solution, and the mixture was stirred at 90° C. for 3hours. After the reaction, water (5 mL) was added and the mixture wasextracted twice with ethyl acetate (5 mL). After being washed withsaturated aqueous sodium chloride, the organic layer was dried overanhydrous sodium sulfate. After concentrating the organic layer, theresidue was purified by column chromatography to obtain ethyl4-cyclopropyl-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A268, 40 mg):

ESI-MS m/z=398 (M⁺+H).

(5) Ethyl4-cyclopropyl-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazol-5-carboxylate(40 mg) was dissolved in a mixed solvent of THF (1 mL) and methanol (0.5mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol) was addedthereto, and then the mixture was stirred at 50° C. for 3 hours. Afterthe reaction, the reaction mixture was neutralized by the addition of 2M aqueous hydrochloric acid (0.2 mL, 0.4 mmol) and was concentrated. Theresidue was purified by HPLC to obtain4-cyclopropyl-1-(napthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A11, 30 mg):

¹H-NMR (DMSO-d₆) δ: 8.62 (1H, d, J=2.0 Hz), 8.56 (1H, dd, J=4.9, 1.5Hz), 8.05-7.95 (2H, m), 7.89-7.82 (2H, m), 7.60-7.56 (2H, m), 7.45-7.38(2H, m), 6.55 (1H, d, J=6.8 Hz), 6.05 (2H, s), 2.78-2.71 (1H, m),1.04-0.96 (4H, m);

HPLC retention time=8.28 min;

Pred. Mass=370.1550 (M⁺+H, C₂₃H₁₉N₃O₂);

Obs. Mass=370.1548 (M⁺+H).

Example 5 Production of1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylicacid (Compound A13) (Scheme A)

(1) Ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (2.75 g, 11.81mmol) described in Example 1 (1) was dissolved in DMF (20 mL), potassiumcarbonate (3.26 g, 23.62 mmol) and 2,5-dichlorobenzyl bromide (3.4 g,14.17 mmol) were added thereto, and the mixture was stirred at 90° C.for 3 hours. After the reaction, water (50 mL) was added and the mixturewas extracted twice with ethyl acetate (50 mL). The organic layer waswashed with saturated aqueous sodium chloride and subsequently driedover sodium sulfate. After concentrating the organic layer, the residuewas purified by column chromatography to obtain ethyl2-bromo-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylate (1.72g):

¹H-NMR (CDCl₃) δ: 7.34 (1H, d, J=8.8 Hz), 7.20 (1H, dd, J=8.8, 2.4 Hz),6.40 (1H, d, J=2.4 Hz), 5.60 (2H, s), 4.25 (2H, q, J=7.2 Hz), 2.56 (3H,s), 1.27 (3H, t, J=7.1 Hz); ESI-MS m/z=391 (M+H).

(2) Ethyl2-bromo-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylate (1 g,2.55 mmol), pyridin-3-ylboronic acid (627 mg, 5.1 mmol), PdCl₂(dppf)(467 mg, 0.64 mmol), and cesium carbonate (1.66 g, 5.1 mmol) weredissolved in a mixed solvent of 1,4-dioxane (7 mL) and water (1.5 mL),and the solution was stirred at 100° C. for 3 hours under a nitrogenatmosphere. After the reaction, water (50 mL) was added and the mixturewas extracted twice with ethyl acetate (50 mL). The organic layer waswashed with saturated aqueous sodium chloride and subsequently driedover sodium sulfate. After concentrating the organic layer, the residuewas purified by column chromatography to obtain ethyl1-(2,5-dichlorobemzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A269, 565 mg):

¹H-NMR (CDCl₃) δ: 8.69-8.66 (2H, m), 7.82-7.78 (1H, m), 7.37-7.33 (2H,m), 7.26-7.22 (1H, m), 6.66 (1H, d, J=2.4 Hz), 5.53 (2H, s), 4.25 (2H,q, J=7.2 Hz), 2.65 (3H, s), 1.27 (3H, t, J=7.1 Hz);

ESI-MS m/z=391 (M⁺+H).

(3) Ethyl1-(2,5-dichlorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(859 mg, 2.2 mmol) was dissolved in a mixed solvent of THF (8 ml) andmethanol (3 ml), 2 M aqueous sodium hydroxide (2.2 mL, 4.4 mmol) wasadded to the solution, and the mixture was stirred at 50° C. for 3hours. After the reaction, the reaction mixture was neutralized by theaddition of a 2M hydrochloric acid (2.2 mL, 4.4 mmol) and wasconcentrated. The residue was purified by a conventional method toobtain1-(2,5-dichlorobenzyl)-4-methyl-2-(pyridine-3-yl)-1H-imidazole-5-carboxylicacid (Compound A13, 393 mg):

¹H-NMR (DMSO-d₆) δ: 13.01 (1H, s), 8.64-8.61 (2H, m), 7.84 (1H, d, J=7.8Hz), 7.52-7.44 (2H, m), 7.37 (1H, dd, J=8.5, 2.2 Hz), 6.54 (1H, d, J=2.0Hz), 5.55 (2H, s), 2.49 (3H, s);

HPLC retention time=7.33 min;

Pred. Mass=362.0458 (M⁺+H, C₁₇H₁₃Cl₂N₃O₂);

Obs. Mass=362.0455 (M⁺+H).

Example 6 Production of1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylicacid (Compound A19) (Scheme A)

(1) Ethyl 4-trifluoromethyl-1H-imidazole-5-carboxylate (5.73 g, 27mmol), which is publicly known through publication (for example, Journalof Medicinal Chemistry, 2011, 54, 7621-7638), was dissolved inacetonitrile (100 mL), N-bromosuccinimide (5.88 g, 33 mmol) was addedthereto, and the mixture was stirred at 50° C. for 2 hours. After thereaction, acetonitrile was distilled away, saturated aqueous sodiumbicarbonate (50 mL) was added, and mixture was extracted twice withethyl acetate (50 mL). After being washed with saturated aqueousmagnesium chloride, the organic layer was dried over sodium sulfate.After concentrating the organic layer, the residue was purified bycolumn chromatography to obtain ethyl2-bromo-4-trifluoromethyl-1H-imidazole-5-carboxylate (5.71 g):

¹H-NMR (CDCl₃) δ: 4.44 (2H, q, J=7.2 Hz), 1.40 (3H, t, J=7.2 Hz);

ESI-MS m/z=287 (M⁺+H).

(2) Ethyl 2-bromo-4-trifluoromethyl-1H-imidazole-5-carboxylate (1.57 g,5.47 mmol) was dissolved in DMF (11 mL), potassium carbonate (1.51 g,10.9 mmol) and 2,5-dichlorobenzyl bromide (1.58 g, 6.56 mmol) were addedthereto, and the mixture was stirred at 90° C. for 3 hours. After thereaction, water (50 mL) was added and the mixture was extracted twicewith ethyl acetate (50 mL). After being washed with saturated aqueoussodium chloride, the organic layer was dried over sodium sulfate. Afterconcentrating the organic layer, the residue was purified by columnchromatography to obtain ethyl2-bromo-1-(2,5-dichlorobenzyl)-4-trifluoromethyl-1H-imidazole-5-carboxylate(2.07 g):

¹H-NMR (CDCl₃) δ: 7.38 (1H, d, J=8.3 Hz), 7.26-7.23 (1H, m), 6.43 (1H,d, J=2.4 Hz), 5.66 (2H, s), 4.32 (2H, q, J=7.1 Hz), 1.32 (3H, t, J=7.1Hz);

ESI-MS m/z=445 (M⁺+H).

(3) Ethyl2-bromo-1-(2,5-dichlorobenzyl)-4-trifluoromethyl-1H-imidazole-5-carboxylate(2.05 g, 4.6 mmol), pyridin-3-ylboronic acid (847 mg, 6.89 mmol), PdCl₂(dppf) (673 mg, 0.92 mmol), and cesium carbonate (2.99 g, 9.19 mmol)were dissolved in a mixed solvent of 1,4-dioxane (13 mL) and water (3mL), and the solution was heated and stirred at 100° C. for 3 hoursunder a nitrogen atmosphere. After the reaction, water (50 mL) was addedand the mixture was extracted twice with ethyl acetate (50 mL). Afterbeing washed with a saturated aqueous sodium chloride solution, theorganic layer was dried over sodium sulfate.

After concentrating the organic layer, the residue was purified bycolumn chromatography to obtain ethyl1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-trifluoromethyl-1H-imidazole-5-carboxylate(Compound A270, 1.42 g):

¹H-NMR (CDCl₃) δ: 8.72 (1H, dd, J=4.9, 1.5 Hz), 8.68 (1H, d, J=1.2 Hz),7.85-7.81 (1H, m), 7.41-7.35 (2H, m), 7.28-7.25 (1H, m), 6.64 (1H, d,J=2.0 Hz), 5.60 (2H, s), 4.33 (2H, q, J=7.1 Hz), 1.32 (3H, t, J=7.1 Hz);

ESI-MS m/z=444 (M⁺+H).

(4) Ethyl1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-4-trifluoromethyl-1H-imidazole-5-carboxylate(1.42 g, 3.2 mmol) was dissolved in a mixed solvent of THF (13 ml) andmethanol (3 mL), and 2 M aqueous sodium hydroxide (3.2 mL, 6.4 mmol) wasadded to the solution, and then the mixture was stirred at 50° C. for 3hours. After the reaction, the reaction mixture was neutralized by theaddition of 2 M hydrochloric acid (3.2 mL, 6.4 mmol) and wasconcentrated. The residue was purified by a conventional method toobtain1-(2,5-dichlorobenzyl)-2-(pyridyn-3-yl)-4-trifluoromethyl-1H-imidazole-5-carboxylicacid (Compound A19, 683 mg):

¹H-NMR (DMSO-d₆) δ: 14.13 (1H, s), 8.70-8.66 (2H, m), 7.92 (1H, dt,J=7.8, 2.0 Hz), 7.53-7.47 (2H, m), 7.39 (1H, dd, J=8.8, 2.4 Hz), 6.80(1H, d, J=2.4 Hz), 5.60 (2H, s);

HPLC retention time=9.32 min;

Pred. Mass=416.0175 (M⁺+H, C₁₇H₁₀O₂F₃N₃O₂);

Obs. Mass=416.0175+H).

Example 7 Production of1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylic acid(Compound A45) (Scheme C)

(1) Methyl 1H-imidazole-4-carboxylate (1 g, 7.93 mmol),(2,5-dichlorophenyl)methanol (1.68 g, 9.52 mmol), and triphenylphosphine(3.12 g, 11.89 mmol) were dissolved in THF (15 mL), and a toluenesolution of DIAD (2.4 g, 11.89 mmol) was dropwise added thereto, andthen the mixture was stirred at 50° C. for 2 hours. After the reaction,water (50 mL) was added and the mixture was extracted twice with ethylacetate (50 mL). After being washed with saturated aqueous sodiumchloride, the organic layer was dried over sodium sulfate. Afterconcentrating the organic layer, the residue was purified by columnchromatography to obtain methyl1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate (4 g):

¹H-NMR (CDCl₃) δ: 7.83 (1H, s), 7.67 (1H, s), 7.36 (1H, d, J=8.8 Hz),7.24 (1H, dd, J=8.3, 2.4 Hz), 6.78 (1H, d, J=2.4 Hz), 5.61 (2H, s), 3.83(3H, s);

ESI-MS m/z=285 (M⁺+H).

(2) Methyl 1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate (2.4 g),2,2′-azobis(isobutyronitrile) (AIBN) (69 mg, 0.421 mmol) was dissolvedin carbon tetrachloride (20 mL), and N-bromosuccinimide (3 g, 16.83mmol) was added thereto, and then mixture was stirred at 50° C. for 20hours. After the reaction, water (50 mL) was added and the mixture wasextracted twice with dichloromethane (50 mL). After being washed withaqueous sodium thiosulfate and saturated aqueous sodium chloride, theorganic layer was dried over sodium sulfate. After concentrating theorganic layer, the residue was purified by column chromatography toobtain methyl 2-bromo-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate(890 mg):

¹H-NMR (CDCl₃) δ: 7.83 (1H, s), 7.36 (1H, d, J=8.3 Hz), 7.21 (1H, dd,J=8.8, 2.4 Hz), 6.34 (1H, d, J=2.4 Hz), 5.66 (2H, s), 3.82 (3H, s);

ESI-MS m/z=363 (M⁺+H).

(3) Under a nitrogen atmosphere, methyl2-bromo-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate (100 mg, 0.275mmol), pyridin-3-ylboronic acid (67.5 mg, 0.55 mmol), PdCl₂ (dppf) (40.2mg, 0.055 mmol), and cesium carbonate (179 mg, 0.55 mmol) were dissolvedin a mixed solvent of 1,4-dioxane (1 mL) and water (0.2 mL), and thesolution was stirred at 100° C. for 20 hours. After the reaction, water(5 mL) was added and the mixture was extracted twice with ethyl acetate(5 mL). After being washed with saturated aqueous sodium chloride, theorganic layer was dried over sodium sulfate. After concentrating theorganic layer, the residue was purified by column chromatography toobtain methyl1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A271, 15 mg):

ESI-MS m/z=362 (M⁺+H).

(4) Methyl1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate (15mg) was dissolved in a mixed solvent of THF (1 mL) and methanol (0.5mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol) was addedthereto, and then the mixture was stirred at 50° C. for 3 hours. Afterthe reaction, the reaction mixture was neutralized by the addition of 2M hydrochloric acid (0.2 mL, 0.4 mmol) and was concentrated. The residuewas purified by HPLC to obtain1-(2,5-dichlorobenzyl)-2-(pyridyn-3-yl)-1H-imidazole-5-carboxylic acid(Compound A45, 9.43 mg):

¹H-NMR (DMSO-d₆) δ: 8.71 (2H, s), 7.98 (1H, s), 7.94 (1H, d, J=8.3 Hz),7.57-7.49 (2H, m), 7.39 (1H, dd, J=8.8, 2.4 Hz), 6.54 (1H, d, J=2.4 Hz),5.65 (2H, s);

HPLC retention time=7.25 min;

Pred. Mass=348.0301 (M⁺+H, C₁₆H₁₁Cl₂N₃O₂);

Obs. Mass=348.0296 (M⁺+H).

Example 8 Production of4-chloro-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A88) (Scheme D)

(1) In DMF (70 mL) was dissolved 3-(1H-imidazol-2-yl)pyridine (10 g,68.9 mmol) which is publicly known through publication, potassiumcarbonate (19 g, 138 mmol) and 2,5-dichlorobenzyl bromide (19.83 g, 83mmol) were added thereto, and the mixture was stirred at roomtemperature for 7 hours. After the reaction, water was added and themixture was extracted twice with ethyl acetate (100 mL). After beingwashed with saturated aqueous sodium chloride, the organic layer wasdried over anhydrous sodium sulfate. After concentrating the organiclayer, the residue was purified by column chromatography to obtain3-(1-(2,5-dichlorobenzyl)-1H-imidazol-2-yl)pyridine (12.49 g):

¹H-NMR (DMSO-d₆) δ: 8.71 (1H, d, J=2.0 Hz), 8.58 (1H, dd, J=4.9, 1.5Hz), 7.92 (1H, dt, J=8.1, 2.0 Hz), 7.52-7.36 (4H, m), 7.15 (1H, d, J=1.5Hz), 6.81 (1H, d, J=2.4 Hz), 5.41 (2H, s);

ESI-MS m/z=304 (M⁺+H).

(2) In dichloromethane (65 mL) was dissolved3-(1-(2,5-dichlorobenzyl)-1H-imidazol-2-yl)pyridine (6.4 g, 21.1 mmol),N-bromosuccinimide (3.76 g, 21.1 mmol) was added thereto, and themixture was stirred at room temperature for 16 hours. After thereaction, water was added and the mixture was extracted twice withdichloromethane (100 mL). After being washed with saturated aqueoussodium chloride, the organic layer was dried over anhydrous sodiumsulfate. After concentrating the organic layer, the residue was purifiedby column chromatography to obtain3-(5-bromo-1-(2,5-dichlorobenzyl)-1H-imidazol-2-yl)pyridine (3.5 g):

¹H-NMR (CDCl₃) δ: 8.67-8.63 (2H, m), 7.80 (1H, dt, J=7.8, 2.0 Hz),7.40-7.33 (3H, m), 7.30-7.26 (1H, m), 6.64 (1H, s), 5.28 (2H, s);

ESI-MS m/z=382 (M⁺+H).

(3) Under a nitrogen atmosphere,3-(5-bromo-1-(2,5-dichlorobenzyl)-1H-imidazol-2-yl)pyridine (1.74 g,4.54 mmol), PdCl₂ (dppf) (500 mg, 0.68 mmol), and triethylamine (5.4 mL,39.1 mmol) were dissolved in ethanol (10 mL) and, after replacing theatmosphere with CO gas, the solution was stirred at 70° C. for 16 hours.After the reaction, the solvent was distilled away, water (20 mL) wasadded to the residue, and the mixture was extracted twice with ethylacetate (30 mL). After being washed with saturated aqueous sodiumchloride, the organic layer was dried over anhydrous sodium sulfate.After concentrating the organic layer, and the residue was purified bycolumn chromatography to obtain ethyl1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A272, 1.2 g):

¹H-NMR (CDCl₃) δ: 8.72-8.67 (2H, m), 8.03 (1H, s), 7.82 (1H, td, J=5.0,2.8 Hz), 7.39-7.34 (2H, m), 7.24 (1H, dd, J=8.8, 2.4 Hz), 6.59 (1H, d,J=2.4 Hz), 5.61 (2H, s), 4.28 (2H, q, J=7.2 Hz), 1.31 (3H, t, J=7.1 Hz);

ESI-MS m/z=376 (M⁺+H).

(4) Ethyl1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate (100mg, 0.266 mmol) was dissolved in acetonitrile (0.5 mL), andN-chlorosuccinimide (71 mg, 0.532 mmol) was added thereto, and then themixture was stirred at 60° C. for 2 hours. After the reaction, water (5mL) was added and the mixture was extracted twice with ethyl acetate (5mL). After being washed with saturated aqueous sodium chloride, theorganic layer was dried over anhydrous sodium sulfate. Afterconcentrating the organic layer, the residue was purified by columnchromatography to obtain ethyl4-chloro-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A273, 100 mg):

¹H-NMR (CDCl₃) δ: 8.72-8.67 (2H, m), 7.83 (1H, dt, J=8.1, 2.0 Hz),7.40-7.35 (2H, m), 7.26 (1H, dd, J=8.8, 2.4 Hz), 6.70 (1H, d, J=2.0 Hz),5.58 (2H, s), 4.30 (2H, q, J=7.2 Hz), 1.30 (3H, t, J=7.3 Hz);

ESI-MS m/z=410 (M⁺+H).

(5) Ethyl4-chloro-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(100 mg) was dissolved in a mixed solvent of THF (1 mL) and methanol(0.5 mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol) was addedthereto, and then the mixture was stirred at 50° C. for 3 hours. Afterthe reaction, the reaction mixture was neutralized by the addition of 2M hydrochloric acid (0.2 mL, 0.4 mmol) and was concentrated. The residuewas purified by HPLC to obtain4-chloro-1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A88, 71 mg):

¹H-NMR (DMSO-d₆) δ: 13.57 (1H, s), 8.69-8.64 (2H, m), 7.88 (1H, dt,J=8.1, 2.0 Hz), 7.53-7.48 (2H, m), 7.39 (1H, dd, J=8.5, 2.7 Hz), 6.79(1H, d, J=2.4 Hz), 5.57 (2H, s);

HPLC retention time=8.74 min;

Pred. Mass=381.9911 (M⁺+H, C₁₆H₁₀Cl₃N₃O₂);

Obs. Mass=381.9908 (M⁺+H).

Example 9 Production of1-(2,5-dichlorobenzyl)-4-iodo-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A90) (Scheme F)

(1) In methanol (250 mL) was dissolved3-(1-(2,5-dichlorobenzyl)-1H-imidazol-2-yl)pyridine (16.1 g, 52.9 mmol)obtained in Example 8, iodine (26.9 g, 106 mmol) and silver nitrate(16.5 g, 52.9 mmol) were added thereto, and the mixture was stirred at50° C. for 1 hour. After allowing the reaction mixture to cool, iodine(13.4 g, 52.9 mmol) and silver nitrate (8.2 g, 26.4 mmol) were added,and the mixture was further stirred at 50° C. for 1 hour. After thereaction, the reaction mixture was filtered by using methanol and thefiltrate was concentrated. To the residue were added aqueous sodiumthiosulfate and aqueous sodium hydrogen carbonate, and the mixture wasextracted twice with dichloromethane (100 mL). After being washed withsaturated aqueous sodium chloride, the organic layer was dried overanhydrous sodium sulfate. After concentrating the organic layer, theresidue was purified by column chromatography to obtain3-(1-(2,5-dichlorobenzyl)-4,5-diiodo-1H-imidazol-2-yl)pyridine (5.1 g):

¹H-NMR (CDCl₃) δ: 8.67-8.62 (2H, m), 7.81 (1H, dt, J=8.0, 2.0 Hz),7.40-7.27 (3H, m), 6.66 (1H, d, J=2.4 Hz), 5.32 (2H, s);

ESI-MS m/z=556 (M⁺+H).

(2) Under a nitrogen atmosphere,3-(1-(2,5-dichlorobenzyl)-4,5-diiodo-1H-imidazol-2-yl)pyridine (3.87 g,6.96 mmol) was dissolved in DMF (130 mL) and, at 0° C., a 1 M solution(13.9 mL, 13.9 mmol) of EtMgBr in THF was added dropwise thereto over aperiod of 10 minutes. After being stirred as is for further 10 minutes,the mixture was further stirred at room temperature for 1 hour. Waterwas added to the reaction mixture and the mixture was extracted twicewith ethyl acetate. After being washed with saturated aqueous sodiumchloride, the organic layer was dried over anhydrous sodium sulfate.After concentrating the organic layer, the residue was purified bycolumn chromatography to obtain1-(2,5-dichlorobenzyl)-4-iodo-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde(2.5 g):

¹H-NMR (CDCl₃) δ: 9.69 (1H, s), 8.74-8.68 (2H, m), 7.84 (1H, dt, J=8.1,1.7 Hz), 7.42-7.36 (2H, m), 7.27-7.25 (1H, m), 6.63 (1H, d, J=2.0 Hz),5.61 (2H, s); ESI-MS m/z=458 (M⁺+H).

(3)1-(2,5-Dichlorobenzyl)-4-iodo-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde(50 mg, 0.109 mmol) and 2-methyl-2-butene (23 mg, 0.33 mmol) weredissolved in a mixed solvent of THF (0.5 mL) and t-butanol (0.5 mL), andan aqueous solution (0.25 mL) of sodium chlorite (30 mg, 0.332 mmol) andsodium dihydrogen phosphate (51 mg, 0.327 mmol) was added dropwisethereto, and then the mixture was stirred at room temperature for 16hours. After the reaction, saturated aqueous sodium chloride was addedand the mixture was extracted twice with ethyl acetate (1 mL). Theorganic layer was dried over anhydrous sodium sulfate. Afterconcentrating the organic layer, the residue was purified by HPLC toobtain1-(2,5-dichlorobenzyl)-4-iodo-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A90, 14.2 mg):

¹H-NMR (DMSO-d₆) δ: 8.69-8.64 (2H, m), 7.90 (1H, dt, J=7.8, 2.0 Hz),7.54-7.48 (2H, m), 7.39 (1H, dd, J=8.8, 2.4 Hz), 6.69 (1H, d, J=2.4 Hz),5.57 (2H, s);

HPLC retention time=8.71 min;

Pred. Mass=473.9268 (M⁺+H, C₁₆H₁₀Cl₂IN₃O₂);

Obs. Mass=473.9277 (M⁺+H).

Example 10 Production of1-(2,5-dichlorobenzyl)-4-phenyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A91) (Scheme F)

(1) Under a nitrogen atmosphere,1-(2,5-dichlorobenzyl)-4-iodo-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde(69 mg, 0.151 mmol), phenylboronic acid (22 mg, 0.180 mmol), PdCl₂(dppf) (11 mg, 0.015 mmol), and cesium carbonate (100 mg, 0.31 mmol)were dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (0.5mL), and the solution was stirred at 100° C. for 1 hour. After thereaction, water (5 mL) was added and the mixture was extracted twicewith ethyl acetate (5 mL). After being washed with saturated aqueoussodium chloride, the organic layer was dried over sodium sulfate. Afterconcentrating the organic layer, the residue was purified by columnchromatography to obtain1-(2,5-dichlorobenzyl)-4-phenyl-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde(48.3 mg):

ESI-MS m/z=408 (M⁺+H).

(2)1-(2,5-Dichlorobenzyl)-4-phenyl-2-(pyridin-3-yl)-1H-imidazole-5-carbaldehyde(48.3 mg, 0.118 mmol) and 2-methyl-2-butene (25 mg, 0.36 mmol) weredissolved in a mixed solvent of THF (0.5 mL) and t-butanol (0.5 mL), andan aqueous solution (0.25 mL) of sodium chlorite (32 mg, 0.354 mmol) andsodium dihydrogen phosphate (55 mg, 0.352 mmol) was added dropwisethereto, and then the mixture was stirred at room temperature for 16hours. After the reaction, saturated aqueous sodium chloride was addedand the mixture was extracted twice with ethyl acetate (1 mL). Theorganic layer was dried over sodium sulfate. After concentrating theorganic layer, the residue was purified by HPLC to obtain1-(2,5-dichlorobenzyl)-4-phenyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A91, 20 mg):

¹H-NMR (DMSO-d₆) δ: 8.73 (1H, s), 8.68 (1H, d, J=3.9 Hz), 7.95 (1H, d,J=8.0 Hz), 7.78-7.74 (2H, m), 7.54-7.50 (2H, m), 7.45-7.35 (4H, m), 6.73(1H, d, J=2.0 Hz), 5.61 (2H, s);

HPLC retention time=9.08 min;

Pred. Mass=424.0614 (M⁺+H, C₂₂H₁₅Cl₂N₃O₂);

Obs. Mass=424.0602 (M⁺+H).

Example 11 Production of1-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A108) (Scheme A)

(1) Dimethyl 1H-imidazole-4,5-dicarboxylate (9.6 g, 52 mmol) wasdissolved in acetonitrile (200 mL), and N-bromosuccinimide (13.92 g, 78mmol) was added thereto, and then the mixture was stirred at 50° C. for4 hours. After the reaction, water was added and the mixture wasextracted twice with ethyl acetate. After being washed with saturatedaqueous sodium thiosulfate and saturated aqueous sodium chloride, theorganic layer was dried over anhydrous sodium sulfate. The organic layerwas concentrated to obtain dimethyl2-bromo-1H-imidazole-4,5-dicarboxylate (8.3 g). This material was usedas is in the next reaction without further purification:

¹H-NMR (CDCl₃) δ: 10.56 (1H, s), 3.96 (6H, s);

ESI-MS m/z=263 (M⁺+H).

(2) Under a nitrogen atmosphere, dimethyl2-bromo-1H-imidazole-4,5-carboxylate (2 g, 7.6 mmol) was dissolved inTHF (38 mL) and, at −10° C., a 1 M solution (30 mL) of EtMgBr in THF wasadded dropwise thereto over a period of 10 minutes. After allowing themixture to react for further 30 minutes, the reaction was quenched bythe addition of aqueous ammonium chloride. Water was added and themixture was extracted twice with ethyl acetate. After being washed withsaturated aqueous sodium chloride, the organic layer was dried overanhydrous sodium sulfate. After concentrating the organic layer, theresidue was purified by column chromatography to obtain methyl2-bromo-4-(2-hydroxypropan-2-yl)-1H-imidazole-5-dicarboxylate (830 mg):

¹H-NMR (CDCl₃) δ: 9.78 (1H, s), 3.93 (3H, s), 1.68 (3H, s), 1.61 (3H,s);

ESI-MS m/z=263 (M⁺+H).

(3) Methyl2-bromo-4-(2-hydroxypropan-2-yl)-1H-imidazole-4,5-dicarboxylate (830 mg,3.15 mmol) was dissolved in DMF (3 mL), and potassium carbonate (872 mg,6.31 mmol) and 2,5-dichlorobenzyl bromide (908 mg, 3.79 mmol) were addedthereto, and then the mixture was stirred at 90° C. for 1 hour. Afterthe reaction, water was added and the mixture was extracted twice withethyl acetate. After being washed with saturated aqueous sodiumchloride, the organic layer was dried over anhydrous sodium sulfate.After concentrating the organic layer, the residue was purified bycolumn chromatography to obtain methyl2-bromo-1-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-1H-imidazole-5-carboxylate(673 mg):

¹H-NMR (CDCl₃) δ: 7.37 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=8.8 Hz), 6.46(1H, s), 5.55 (2H, s), 3.77 (3H, s), 1.65 (6H, s);

ESI-MS m/z=421 (M⁺+H).

(4) Methyl2-bromo-1-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-1H-imidazole-5-carboxylate(100 mg, 0.237 mmol), pyridin-3-ylboronic acid (58.2 mg, 0.474 mmol),cesium carbonate (154 mg, 0.474 mmol), and PdCl₂ (dppf) (34.7 mg, 0.047mmol) were dissolved in a mixed solvent of dioxane (1 mL) and water (0.2mL). Under a nitrogen atmosphere, the solution was heated and stirred at100° C. for 3 hours. After cooling, the reaction mixture wasconcentrated under reduced pressure and ethyl acetate was added to theresidue. The organic layer was washed with water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, andsubsequently concentrated under reduced pressure. The residue waspurified by column chromatography to obtain methyl1-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(Compound A274, 71 mg):

ESI-MS m/z=420 (M⁺+H).

(5) Methyl1-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate(71 mg, 0.169 mmol) was dissolved in a mixed solvent of THF (1 mL) andmethanol (0.5 mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol)was added thereto, and then the mixture was stirred at 50° C. for 2hours. After the reaction, the reaction mixture was neutralized by theaddition of 2 M hydrochloric acid (0.2 mL, 0.4 mmol) and wasconcentrated. The residue was purified by HPLC to obtain1-(2,5-dichlorobenzyl)-4-(2-hydroxypropan-2-yl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylicacid (Compound A108, 61 mg):

¹H-NMR (DMSO-d₆) δ: 8.71-8.65 (2H, m), 7.91 (1H, d, J=7.8 Hz), 7.56-7.48(2H, m), 7.39 (1H, dd, J=8.5, 2.2 Hz), 6.56 (1H, d, J=1.5 Hz), 5.59 (2H,s), 1.62 (6H, s);

HPLC retention time=8.16 min;

Pred. Mass=406.0720 (M⁺+H, C₁₉H₁₇Cl₂N₃O₃);

Obs. Mass=406.0725 (M⁺+H).

Example 12 Production of3-(1-(2,5-dichlorobenzyl)-5-(1H-tetrazol-5-yl)-1H-imidazol-2-yl)pyridine(Compound A110) (Scheme G)

(1) Under a nitrogen atmosphere,3-(5-bromo-1-(2,5-dichlorobenzyl)-1H-imidazol-2-yl)pyridine (300 mg,0.784 mmol) obtained in Example 8, ZnCN₂ (138 mg, 1.174 mmol),tetrakis(triphenylphosphine)palladium (272 mg, 0.117 mmol) weredissolved in DMF (3 mL), and the mixture was stirred at 100° C. for 16hours. After the reaction, water was added and the mixture was extractedtwice with ethyl acetate (10 mL). After being washed with saturatedaqueous sodium chloride, the organic layer was dried over anhydroussodium sulfate. After concentrating the organic layer, the residue waspurified by column chromatography to obtain1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carbonitrile (83mg):

¹H-NMR (CDCl₃) δ: 8.74-8.71 (2H, m), 7.92 (1H, s), 7.86 (1H, dt, J=8.3,2.0 Hz), 7.43-7.38 (2H, m), 7.31 (1H, dd, J=8.3, 2.4 Hz), 6.67 (1H, d,J=2.4 Hz), 5.41 (2H, s);

ESI-MS m/z=329 (M⁺+H).

(2) In DMF (1 mL) was dissolved1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carbonitrile (83mg, 0.252 mmol), and triethylamine hydrochloride (34.7 mg, 0.252 mmol)and sodium azide (82 mg, 1.26 mmol) were added thereto, and then themixture was stirred at 140° C. for 3 hours. After filtering the reactionsolution, the filtrate was purified by HPLC to obtain3-(1-(2,5-dichlorobenzyl)-5-(1H-tetrazol-5-yl)-1H-imidazol-2-yl)pyridine(Compound A110, 80 mg):

¹H-NMR (DMSO-d₆) δ: 8.75 (1H, d, J=2.0 Hz), 8.69-8.65 (1H, m), 8.00-7.96(2H, m), 7.56-7.48 (2H, m), 7.35 (1H, dd, J=8.3, 2.4 Hz), 6.51 (1H, d,J=2.4 Hz), 5.83 (2H, s);

HPLC retention time=7.97 min;

Pred. Mass=372.0526 (M⁺+H, C₁₆H₁₁Cl₂N₇);

Obs. Mass=372.0527 (M⁺+H).

Example 13 Production of1-(2,5-dichlorobenzyl)-4-methyl-N-(methylsulfonyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxamide(Compound A111) (Scheme A)

(1) In dichloromethane (1 mL) were dissolved1-(2,5-dichlorobenzyl)-4-methyl-2-(pyridin-3-yl)-1H-imidazole-5-carboxlicacid (30 mg, 0.083 mmol), methanesulfonamide (15.76 mg, 0.166 mmol) andDMAP (20.24 mg, 0.166 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (31.8mg, 0.166 mmol) was added thereto, and the mixture was stirred at roomtemperature for 16 hours. Purification by HPLC was performed to obtain1-(2,5-dichlorobenzyl)-4-methyl-N-(methylsulfonyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxamide(Compound A111, 18 mg):

¹H-NMR (DMSO-d₆) δ: 8.74 (1H, d, J=2.0 Hz), 8.69 (1H, dd, J=4.9, 2.0Hz), 7.99 (1H, dt, J=8.0, 1.8 Hz), 7.58-7.53 (1H, m), 7.46 (1H, d, J=8.3Hz), 7.38 (1H, dd, J=8.5, 2.7 Hz), 6.78 (1H, d, J=2.4 Hz), 5.50 (2H, s),3.13 (3H, s), 2.45 (3H, s);

HPLC retention time=7.76 min;

Pred. Mass=439.0393 (M⁺+H, C₁₈H₁₆Cl₂N₄O₃S);

Obs. Mass=439.0397 (M⁺+H).

Example 14 Production of2-(5-fluoropyridin-3-yl)-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylicacid (Compound A119) (Scheme A)

(1) Ethyl2-bromo-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylate(1.26 g, 3.39 mmol) described in Example 1 (2),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (800mg, 3.59 mmol), PdCl₂ (dppf) (496 mg, 0.678 mmol), and cesium carbonate(2.2 g, 6.78 mmol) were dissolved in a mixed solvent of 1,4-dioxane (9mL) and water (2 mL), and the solution was stirred at 100° C. for 3hours under a nitrogen atmosphere. After the reaction, water (50 mL) wasadded and the mixture was extracted twice with ethyl acetate (50 mL).After being washed with saturated aqueous sodium chloride, the organiclayer was dried over anhydrous sodium sulfate. After concentrating theorganic layer, the residue was purified by column chromatography toobtain ethyl2-(5-fluoropyridin-3-yl)-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylate(Compound A275, 1.2 g):

¹H-NMR (CDCl₃) δ: 8.53 (1H, s), 8.44 (1H, d, J=2.9 Hz), 7.94-7.85 (2H,m), 7.80 (1H, d, J=8.3 Hz), 7.63-7.53 (3H, m), 7.38 (1H, t, J=7.8 Hz),6.70 (1H, d, J=6.8 Hz), 6.06 (2H, s), 4.14 (2H, q, J=7.2 Hz), 2.67 (3H,s), 1.09 (3H, t, J=7.2 Hz);

ESI-MS m/z=390 (M⁺+H).

(2) Ethyl2-(5-fluoropyridin-3-yl)-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylate(1.2 g, 3.08 mmol) was dissolved in a mixed solvent of THF (12 mL) andmethanol (3 mL), 2 M aqueous sodium hydroxide (3 mL, 6 mmol) was addedthereto, and the mixture was stirred at 40° C. for 3 hours. After thereaction, the reaction mixture was neutralized by the addition of 2 Mhydrochloric acid (3 mL, 6 mmol) and was subsequently concentrated. Theresidue was purified by a conventional method to obtain2-(5-fluoropyridin-3-yl)-4-methyl-1-(naphthalen-1-ylmethyl)-1H-imidazole-5-carboxylicacid (Compound A119, 648 mg):

¹H-NMR (DMSO-d₆) δ: 12.95 (1H, s), 8.58 (1H, d, J=2.9 Hz), 8.48 (1H, s),8.06-7.95 (2H, m), 7.85-7.80 (2H, m), 7.61-7.57 (2H, m), 7.40 (1H, t,J=7.6 Hz), 6.52 (1H, d, J=7.3 Hz), 6.12 (2H, s), 2.53 (3H, s);

HPLC retention time=8.53 min;

Pred. Mass=362.1299 (M⁺+H, C₂₁H₁₆FN₃O₂);

Obs. Mass=362.1300 (M⁺+H).

Example 15 Production of2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylicacid (Compound A191) (Scheme E)

(1) Dimethyl 2-bromo-1H-imidazole-4,5-carboxylate (1.1 g, 4.18 mmol)obtained in Example 11 was dissolved in DMF (4 mL), and potassiumcarbonate (1.15 g, 8.36 mmol) and 2,5-dichlorobenzyl bromide (1.3 g,5.44 mmol) were added thereto, and then the mixture was stirred at 100°C. for 2 hours. After the reaction, water was added and the mixture wasextracted twice with ethyl acetate. After being washed with saturatedaqueous sodium chloride, the organic layer was dried over anhydroussodium sulfate. After concentrating the organic layer, the residue waspurified by column chromatography to obtain2-bromo-1-(2,5-dichlorobenzyl)-1H-imidazole-4,5-dicarboxylate (1.54 g):

¹H-NMR (CDCl₃) δ: 7.36 (1H, d, J=8.8 Hz), 7.24 (1H, dd, J=8.8, 3.0 Hz),6.52 (1H, d, J=2.4 Hz), 5.54 (2H, s), 3.96 (3H, s), 3.85 (3H, s);

ESI-MS m/z=421 (M⁺+H).

(2) Dimethyl2-bromo-1-(2,5-dichlorobenzyl)-1H-imidazole-4,5-dicarboxylate (300 mg,0.711 mmol), (5-chloropyridyn-3-yl)boronic acid (244 mg, 1.422 mmol),cesium carbonate (463 mg, 1.422 mmol) and PdCl₂ (dppf) (104 mg, 0.142mmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.5mL). The solution was heated and stirred at 100° C. for 3 hours under anitrogen atmosphere. After cooling, the reaction mixture wasconcentrated under reduced pressure. To the residue was added ethylacetate and the organic layer was washed with water and saturatedaqueous sodium chloride. After being dried over anhydrous magnesiumsulfate, the organic layer was concentrated under reduced pressure. Theresidue was purified by column chromatography to obtain dimethyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-4,5-dicarboxylate(Compound A276, 168 mg):

¹H-NMR (CDCl₃) δ: 8.66 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.0 Hz), 7.91(1H, t, J=2.0 Hz), 7.36 (1H, d, J=8.3 Hz), 7.29-7.26 (1H, in), 6.72 (1H,d, J=2.4 Hz), 5.51 (2H, s), 3.99 (3H, s), 3.86 (3H, s);

ESI-MS m/z=454 (M⁺+H).

(3) Dimethyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-4,5-dicarboxylate(168 mg, 0.369 mmol) was dissolved in THF (3 mL), a 1 M solution ofdiisobutylaluminum hydride (DIBAL-H) (0.739 mL, 0.739 mmol) was addeddropwise thereto over a period of 5 minutes at −40° C. under a nitrogenatmosphere, and the mixture was stirred as is for 5 hours. After beingallowed to warm to room temperature, the reaction was quenched withaqueous ammonium chloride, followed by the addition of water, and themixture was extracted twice with ethyl acetate. After being washed withsaturated aqueous sodium chloride, the organic layer was dried overanhydrous sodium sulfate. After concentrating the organic layer, theresidue was purified by column chromatography to obtain methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylate(Compounds A277, 57 mg):

¹H-NMR (CDCl₃) δ: 8.65 (1H, d, J=2.4 Hz), 8.50 (1H, d, J=2.0 Hz), 7.91(1H, t, J=2.2 Hz), 7.39 (1H, d, J=8.8 Hz), 7.27 (1H, dd, J=8.3, 2.4 Hz),6.63 (1H, d, J=2.4 Hz), 5.59 (2H, s), 4.99-4.96 (2H, m), 3.85 (3H, s),3.21 (1H, t, J=5.6 Hz);

ESI-MS m/z=426 (M⁺+H).

(4) Methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylate(57 mg, 0.134 mmol) was dissolved in a mixed solvent of THF (1 mL) andmethanol (0.5 mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol)was added thereto, and then the mixture was stirred at 50° C. for 2hours. After the reaction, the reaction mixture was neutralized by theaddition of 2 M hydrochloric acid (0.2 mL, 0.4 mmol) and wasconcentrated. The residue was purified by HPLC to obtain2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylicacid (Compound A191, 35 mg):

¹H-NMR (DMSO-d₆) δ: 8.72 (1H, d, J=2.4 Hz), 8.56 (1H, d, J=2.0 Hz), 8.04(1H, t, J=2.0 Hz), 7.51 (1H, d, J=8.8 Hz), 7.39 (1H, dd, J=8.3, 2.4 Hz),6.60 (1H, d, J=2.4 Hz), 5.64 (2H, s), 4.71 (2H, s);

HPLC retention time=8.81 min;

Pred. Mass=412.0017 (M⁺+H, C₁₇H₁₂Cl₃N₃O₃);

Obs. Mass=412.0018 (M⁺+H).

Example 16 Production of2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((diethylamino)methyl)-1H-imidazole-5-carboxylicacid (Compound A193) (Scheme E)

(1) Methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylate(500 mg, 1.17 mmol) was dissolved in dichloromethane (5 mL), andtribromophosphine (317 mg, 1.17 mmol) was added thereto, and then themixture was stirred at room temperature for 2 hours. After the reaction,water was added and the mixture was extracted twice with ethyl acetate.After being washed with saturated aqueous sodium chloride, the organiclayer was dried over anhydrous sodium sulfate. The organic layer wasconcentrated to obtain methyl4-(bromomethyl)-2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate(500 mg). This material was used as is for the next reaction withoutfurther purification.

(2) Methyl4-(bromomethyl)-2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate(90 mg, 0.184 mmol) was dissolved in DMF (1 mL), and potassium carbonate(50 mg, 0.368 mmol) and diethylamine (26.9 mg, 0.368 mmol) were addedthereto, and then the mixture was stirred at 40° C. for 3 hours. Afterthe reaction, water was added, the reaction mixture was extracted twicewith ethyl acetate, and the organic layer was dried over anhydroussodium sulfate. The organic layer was concentrated to obtain methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((diethylamino)methyl)-1H-imidazole-5-carboxylate(Compound A278, 100 mg). This material was used as is for the nextreaction without further purification:

ESI-MS m/z=481 (M⁺+H).

(3) Methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((diethylamino)methyl)-1H-imidazole-5-carboxylate(100 mg) was dissolved in a mixed solvent of THF (1 mL) and methanol(0.5 mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol) was addedthereto, and then the mixture was stirred at 50° C. for 2 hours. Afterthe reaction, the reaction mixture was neutralized by the addition of 2M hydrochloric acid (0.2 mL, 0.4 mmol) and was concentrated. The residuewas purified by HPLC to obtain2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-((diethylamino)methyl)-1H-imidazole-5-carboxylicacid (Compound A193, 55 mg):

¹H-NMR (DMSO-d₆) δ: 9.58 (1H, s), 8.76 (1H, d, J=2.4 Hz), 8.61 (1H, d,J=2.0 Hz), 8.10 (1H, t, J=2.2 Hz), 7.51 (1H, d, J=8.8 Hz), 7.39 (1H, dd,J=8.3, 2.4 Hz), 6.69 (1H, d, J=2.4 Hz), 5.70 (2H, s), 4.60 (2H, d, J=4.4Hz), 3.35-3.19 (4H, m), 1.27 (6H, t, J=7.3 Hz);

HPLC retention time=8.55 min;

Pred. Mass=467.0803 (M⁺+H, C₂₁H₂₁Cl₃N₄O₂);

Obs. Mass=467.0806 (M⁺+H).

Example 17 Production of2-(5-bromopyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylicacid (Compound A205) (Scheme C)

(1) Ethyl1-(2,5-dichlorobenzyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxylate (50mg, 0.133 mmol) was dissolved in DMF (1 mL), and N-bromosuccinimide (48mg, 0.266 mmol) was added thereto, and then the mixture was stirred at100° C. for 2 hours. After the reaction, water (5 mL) was added and themixture was extracted twice with ethyl acetate (5 mL). After beingwashed with saturated aqueous sodium chloride, the organic layer wasdried over sodium sulfate. After concentrating the organic layer, theresidue was purified by column chromatography to obtain ethyl2-(5-bromopyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate(Compound A279, 39 mg):

¹H-NMR (CDCl₃) δ: 8.74 (1H, d, J=2.0 Hz), 8.53 (1H, d, J=1.5 Hz),8.05-8.01 (2H, m), 7.38 (1H, d, J=8.8 Hz), 7.25 (1H, dd, J=9.0, 2.2 Hz),6.59 (1H, d, J=2.0 Hz), 5.63 (2H, s), 4.29 (2H, q, J=7.2 Hz), 1.32 (3H,t, J=7.3 Hz);

ESI-MS m/z=454 (M⁺+H).

(2) Ethyl2-(5-bromopyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylate(39 mg) was dissolved in a mixed solvent of THF (1 mL) and methanol (0.5mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol) was addedthereto, and then the mixture was stirred at 50° C. for 3 hours. Afterthe reaction, the reaction mixture was neutralized by the addition of 2M hydrochloric acid (0.2 mL, 0.4 mmol) and was concentrated. The residuewas purified by HPLC to obtain2-(5-bromopyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-imidazole-5-carboxylicacid (Compound A205, 23 mg):

¹H-NMR (DMSO-d₆) δ: 13.23 (1H, s), 8.79 (1H, d, J=2.0 Hz), 8.61 (1H, d,J=2.0 Hz), 8.15 (1H, t, J=2.2 Hz), 7.93 (1H, s), 7.51 (1H, d, J=8.8 Hz),7.38 (1H, dd, J=8.3, 2.4 Hz), 6.56 (1H, d, J=2.4 Hz), 5.70 (2H, s);

HPLC retention time=9.99 min;

Pred. Mass=425.9406 (M⁺+H, C₁₆H₁₀BrCl₂N₃O₂);

Obs. Mass=425.9404 (M⁺+H).

Example 18 Production of2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylicacid (Compound A207) (Scheme E)

(1) Methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylate(620 mg, 1.45 mmol) was dissolved in dichloromethane (10 mL), andmanganese dioxide (1.426 g, 16.41 mmol) was added thereto, and then themixture was stirred at room temperature for 96 hours. After thereaction, the reaction mixture was filtered through celite and theresidue was washed with dichloromethane. After concentrating thesolution, the residue was purified by column chromatography to obtainmethyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-formyl-1H-imidazole-5-carboxylate(413 mg):

¹H-NMR (CDCl₃) δ: 10.51 (1H, s), 8.68 (1H, d, J=2.4 Hz), 8.50 (1H, d,J=2.0 Hz), 7.98 (1H, t, J=2.2 Hz), 7.40 (1H, d, J=8.3 Hz), 7.29 (1H, dd,J=8.8, 2.4 Hz), 6.59 (1H, d, J=2.4 Hz), 5.66 (2H, s), 3.97 (3H, s);

ESI-MS m/z=424 (M⁺+H).

(2) Under a nitrogen atmosphere, methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-formyl-1H-imidazole-5-carboxylate(100 mg, 0.235 mmol) was dissolved in dichloromethane (1 mL), anddiethylaminosulfur trifluoride (DAST) (49.3 mg, 0.306 mmol) was addedthereto, and then the mixture was stirred at room temperature for 6hours. After the reaction, water was added, followed by the addition ofan aqueous sodium hydrogen carbonate solution, and the mixture wasextracted twice with ethyl acetate. After being washed with saturatedaqueous sodium chloride, the organic layer was dried over sodiumsulfate. After concentrating the organic layer, the residue was purifiedby column chromatography to obtain methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylate(Compound A280, 86 mg):

¹H-NMR (CDCl₃) δ: 8.67 (1H, d, J=2.4 Hz), 8.49 (1H, d, J=2.0 Hz), 7.95(1H, t, J=2.2 Hz), 7.39 (1H, d, J=8.8 Hz), 7.28 (1H, dd, J=8.8, 2.2 Hz),7.21 (1H, t, J=54.1 Hz), 6.60 (1H, d, J=2.4 Hz), 5.63 (2H, s), 3.91 (3H,s);

ESI-MS m/z=446 (M⁺+H).

(3) Methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylate(86 mg) was dissolved in a mixed solvent of THF (1 mL) and methanol (0.5mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol) was addedthereto, and then the mixture was stirred at 50° C. for 7 hours. Afterthe reaction, the reaction mixture was neutralized with 2 M hydrochloricacid (0.2 mL, 0.4 mmol) and was concentrated. The residue was purifiedby HPLC to obtain2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylicacid (Compound A207, 42 mg):

¹H-NMR (DMSO-d₆) δ: 14.16 (1H, s), 8.75 (1H, d, J=2.4 Hz), 8.58 (1H, d,J=2.0 Hz), 8.07 (1H, t, J=2.2 Hz), 7.53-7.20 (3H, m), 6.75 (1H, d, J=2.4Hz), 5.66 (2H, s);

HPLC retention time=11.04 min;

Pred. Mass=431.9879 (M⁺+H, C₁₇H₁₀Cl₃F₂N₃O₂);

Obs. Mass=431.9878 (M⁺+H).

Example 19 Production of2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-ethynyl-1H-imidazole-5-carboxylicacid (Compound A209) (Scheme E)

(1) Methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-formyl-1H-imidazole-5-carboxylate(70 mg, 0.165 mmol) was dissolved in methanol (2 mL), and potassiumcarbonate (45.6 mg, 0.33 mmol) and dimethyl(1-diazo-2-oxopropyl)phosphonate (44.3 mg, 0.231 mmol) were addedthereto, and then the mixture was stirred at room temperature for 16hours. After the reaction, water was added and the mixture was extractedtwice with ethyl acetate. After being washed with saturated aqueoussodium chloride, the organic layer was dried over sodium sulfate. Afterconcentrating the organic layer, the residue was purified by columnchromatography to obtain methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-ethynyl-1H-imidazole-5-carboxylate(Compound A281, 51 mg):

ESI-MS m/z=420 (M⁺+H).

(2) Methyl2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-ethynyl-1H-imidazole-5-carboxylate(51 mg) was dissolved in a mixed solvent of THF (1 mL) and methanol (0.5mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol) was addedthereto, and then mixture was stirred at 50° C. for 3 hours. After thereaction, the reaction mixture was neutralized by the addition of 2 Mhydrochloric acid (0.2 mL, 0.4 mmol) and was concentrated. The residuewas purified by HPLC to obtain2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-ethynyl-1H-imidazole-5-carboxylicacid (Compound A209, 35 mg):

¹H-NMR (DMSO-d₆) δ: 13.59 (1H, s), 8.73 (1H, d, J=2.0 Hz), 8.57 (1H, d,J=1.5 Hz), 8.06 (1H, t, J=2.2 Hz), 7.48 (1H, d, J=8.3 Hz), 7.38 (1H, d,J=8.8 Hz), 6.73 (1H, s), 5.62 (2H, s), 4.44 (1H, s);

HPLC retention time=10.67 min;

Pred. Mass=405.9911 (M⁺+H, C₁₈H₁₀Cl₃N₃O₂);

Obs. Mass=405.9922 (M⁺+H).

Example 20 Production of2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-furo[3,4-d]imidazol-6(4H)-one(Compound A221) (Scheme E)

(1)2-(5-Chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-4-(hydroxymethyl)-1H-imidazole-5-carboxylicacid (100 mg, 0.242 mmol) was dissolved in DMF (1 mL), and HATU (138 mg,0.364 mmol) and triethylamine (49 mg, 0.485 mmol) were added thereto,and then the mixture was stirred at room temperature for 1 hour. Thereaction mixture was purified by HPLC to obtain2-(5-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1H-furo[3,4-d]imidazole-6(4H)-one(Compound A221, 38 mg):

¹H-NMR (DMSO-d₆) δ: 8.79 (1H, d, J=2.2 Hz), 8.75 (1H, d, J=2.0 Hz), 8.23(1H, t, J=2.2 Hz), 7.47-7.37 (2H, m), 7.30 (1H, d, J=2.0 Hz), 5.51 (2H,s), 5.34 (2H, s);

HPLC retention time=11.16 min;

Pred. Mass=393.9911 (M⁺+H, C₁₇H₁₀Cl₃N₃O₂);

Obs. Mass=393.9911 (M⁺+H).

Example 21 Production of1-(2,5-dichlorobenzyl)-4-methyl-2-((2-methylpyridin-3-yl)oxy)-1H-imidazole-5-carboxylicacid (Compound A252) (Scheme H)

(1) Ethyl2-bromo-1-(2,5-dichlorobenzyl)-4-methyl-1H-imidazole-5-carboxylate (60mg, 0.153 mmol) was dissolved in DMF (1 mL), and potassium carbonate (43mg, 0.306 mmol) and 2-methylpyridin-3-ol (25 mg, 0.23 mmol) were addedthereto, and then the mixture was stirred at 120° C. for 12 hours. Afterthe reaction, water (5 mL) was added and the mixture was extracted twicewith ethyl acetate (5 mL). After being washed with saturated aqueoussodium chloride, the organic layer was dried over sodium sulfate. Afterconcentrating the organic layer, the residue was purified by columnchromatography to obtain ethyl1-(2,5-dichlorobenzyl)-4-methyl-2-((2-methylpyridin-3-yl)oxy-1H-imidazole-5-carboxylate(Compound A282, 44 mg):

ESI-MS m/z=420 (M⁺+H).

(2) Ethyl1-(2,5-dichlorobenzyl)-4-methyl-2-((2-methylpyridin-3-yl)oxy-1H-imidazole-5-carboxylate(44 mg, 0.105 mmol) was dissolved in a mixed solvent of THF (1 mL) andmethanol (0.5 mL), and 2 M aqueous sodium hydroxide (0.2 mL, 0.4 mmol)was added thereto, and then the mixture was stirred at 50° C. for 7hours. After the reaction, the reaction mixture was neutralized by theaddition of 2 M hydrochloric acid (0.2 mL, 0.4 mmol) and wasconcentrated. The residue was purified by HPLC to obtain1-(2,5-dichlorobenzyl)-4-methyl-2-((2-methylpyridin-3-yl)oxy)-1H-imidazole-5-carboxylicacid (Compound A252, 30 mg):

¹H-NMR (DMSO-d₆) δ: 8.43 (1H, dd, J=4.9, 1.0 Hz), 7.95 (1H, d, J=8.3Hz), 7.58-7.40 (3H, m), 6.77 (1H, d, J=2.4 Hz), 5.55 (2H, s), 2.33 (3H,s), 2.28 (3H, s);

HPLC retention time=8.20 min;

Pred. Mass=392.0563 (M⁺+H, C₁₈H₁₅Cl₂N₃O₃);

Obs. Mass=392.0570 (M⁺+H).

Compounds having compound numbers A1 to A266 were synthesized in amanner similar to any of Example 1 to Example 21.

TABLE 13 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 22 A1 A 7.18 322.1552322.1550 C₁₉H₁₉N₃O₂ (DMSO-d6) δ: 12.83 (1H, s), 8.63 (1H, dd, J = 2.2,0.7 Hz), 8.60 (1H, dd, J = 4.9, 1.5 Hz), 7.85 (1H, dt, J = 7.8, 2.0 Hz),7.44 (1H, dd, J = 7.3, 4.9 Hz), 7.05 (1H, d, J = 7.8 Hz), 6.93 (1H, d, J= 7.3 Hz), 6.16 (1H, s), 5.50 (2H, s), 2.49 (3H, s), 2.13 (3H, s), 2.12(3H, s). 23 A3 A 9.55 372.1704 372.1707 C₂₃H₂₁N₃O₂ (CDCl3) δ: 8.78 (1H,d, J = 2.0 Hz), 8.58 (1H, dd, J = 4.9, 1.5 Hz), 7.93-7.85 (2H, m),7.82-7.77 (2H, m), 7.57-7.53 (2H, m), 7.38 (1H, t, J = 7.6 Hz),7.24-7.20 (1H, m), 6.73 (1H, d, J = 6.3 Hz), 6.03 (2H, s), 4.13 (2H, q,J = 7.2 Hz), 2.67 (3H, s), 1.07 (3H, t, J = 7.1 Hz). 24 A4 A 7.02358.1548 358.1550 C₂₂H₁₉N₃O₂ 25 A5 A 7.78 364.1119 364.1114 C₂₀H₁₇N₃O₂S(DMSO-d6) δ: 8.77 (1H, dd, J = 2.0, 1.5 Hz), 8.62 (1H, dd, J = 4.9, 1.5Hz), 8.01 (1H, dt, J = 8.0, 2.0 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.48 (1H,dd, J = 8.3, 4.0 Hz), 7.20 (1H, t, J = 8.0 Hz), 7.10 (1H, d, J = 6.8Hz), 6.70 (1H, s), 6.00 (2H, s), 2.64 (3H, s), 2.49 (3H, s). 26 A6 A8.23 418.0828 418.0832 C₂₀H₁₄F₃N₃O₂S (DMSO-d6) δ: 8.73 (1H, d, J = 2.0Hz), 8.64 (1H, dd, J = 4 .9, 1.5 Hz), 8.40 (1H, d, J = 8.3 Hz), 7.98(1H, dt, J = 8.3, 2.0 Hz), 7.88 (1H, d, J = 7.5 Hz), 7.58 (1H, t, J =7.5 Hz), 7.50 (1H, dd, J = 8.0, 4.9 Hz), 7.17 (1H, s), 5.75 (2H, s),2.56 (3H, s). 27 A8 B 7.88 428.0062 428.0063 C₁₉H₁₄BrN₃O₂S (DMSO-d6) δ:8.75 (1H, d, J = 1.5 Hz), 8.65 (1H, dd, J = 4.9, 1.5 Hz), 8.04 (1H, d, J= 7.8 Hz), 7.99 (1H, dt, J = 7.8, 1.5 Hz), 7.65 (1H, d, J = 7.8 Hz),7.51 (1H, dd, J = 7.8, 4.9 Hz), 7.29 (1H, t, J = 7.8 Hz), 6.98 (1H, s),6.11 (2H, s), 2.54 (3H, s).

TABLE 14 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 28 A10 B 7.76 358.1541358.1550 C₂₂H₁₉N₃O₂ (DMSO-d6) δ: 8.68 (1H, d, J = 2.0 Hz), 8.59 (1H, dd,J = 4.9, 1.5 Hz), 8.04-7.91 (3H, m), 7.84 (1H, d, J = 8.3 Hz), 7.60-7.56(2H, m), 7.45-7.40 (2H, m), 6.56 (1H, d, J = 7.3 Hz), 6.08 (2H, s), 2.98(2H, q, J = 7.5 Hz) 1.28 (3H, t, J = 7.6 Hz). 29 A12 C 7.28 330.1234330.1237 C₂₀H₁₅N₃O₂ 30 A14 B 7.79 376.0618 376.0614 C₁₈H₁₅Cl₂N₃O₂(DMSO-d6) δ: 12.99 (1H, brs), 8.63 (2H, d, J = 3.4 Hz), 7.85 (1H, dt, J= 8.0, 2.0 Hz), 7.51-7.45 (2H, m), 7.38 (1H, dd, J = 8.5, 2.2 Hz), 6.49(1H, s), 5.57 (2H, s), 2.92 (2H, dd, J = 14.9, 7.4 Hz), 1.23 (3H, t, J =7.6 Hz) 31 A15 B 8.50 388.0607 388.0614 C₁₉H₁₅Cl₂N₃O₂ (DMSO-d6) δ: 8.63(1H, dd, J = 4.9, 1.5 Hz), 8.58 (1H, d, J = 2.0 Hz), 7.80 (1H, dt, J =8.1, 2.0 Hz), 7.51 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 7.8, 4.9 Hz),7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.55 (1H, d, J = 2.4 Hz), 5.53 (2H, s),2.74-2.68 (1H, m), 0.99-0.93 (4H, m). 32 A16 A 7.26 350.0952 350.0958C₁₉H₁₅N₃O₂S (DMSO-d6 ) δ: 8.76 (1H, d, J = 2.4 Hz), 8.66 (1H, dd, J =4.9, 1.5 Hz), 8.01 (1H, dt, J = 8.0, 2.0 Hz), 7.99-7.96 (1H, m),7.72-7.69 (1H, m), 7.51 (1H, dd, J = 7.8, 4.9 Hz), 7.42-7.38 (2H, m),7.04 (1H, s), 5.82 (2H, s), 2.53 (3H, s). 33 A17 A 7.93 358.1539358.1550 C₂₂H₁₉N₃O₂ (DMSO-d6) δ: 8.70 (1H, d, J = 2.4 Hz), 8.62 (1H, dd,J = 4.9, 1.0 Hz), 8.07 (1H, dd, J = 7.3, 2.0 Hz), 8.02 (1H, dd, J = 7.8,1.5 Hz), 7.95 (1H, dt, J = 8.0, 1.7 Hz), 7.64-7.58 (2H, m), 7.46 (1H,dd, J = 7.8, 4.9 Hz), 7.26 (1H, d, J = 7.3 Hz), 6.50 (1H, d, J = 8.0Hz), 6.06 (2H, s), 2.61 (3H, s), 2.57 (3H, s).

TABLE 15 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 34 A18 B 8.79 384.1700384.1707 C₂₄H₂₁N₃O₂ (DMSO-d6) δ: 8.64 (1H, s), 8.58 (1H, d, J = 4.9 Hz),8.06 (1H, d, J = 8.3 Hz), 8.02 (1H, d, J = 7.8 Hz), 7.89 (1H, d, J = 7.8Hz), 7.64-7.57 (2H, m), 7.43 (1H, dd, J = 7.8, 4.9 Hz), 7.27 (1H, d, J =6.8 Hz), 6.45 (1H, d, J = 7.3 Hz), 6.02 (2H, s), 2.78-2.71 (1H, m), 2.60(3H, s), 1.03-0.96 (4H, m). 35 A20 A 9.24 398.1104 398.1111 C₂₁H₁₄F₃N₃O₂36 A21 A 8.91 412.1274 412.1267 C₂₂H₁₆F₃N₃O₂ 37 A22 A 9.06 404.0679404.0675 C₁₉H₁₂F₃N₃O₂S 38 A23 D 9.11 378.1018 378.1004 C₂₁H₁₆ClN₃O₂(DMSO-d6) δ: 8.67 (1H, s), 8.60 (1H, d, J = 4.9 Hz), 8.12-7.97 (2H, m),7.91 (1H, dt, J = 7.8, 1.5 Hz), 7.65-7.58 (2H, m), 7.43 (1H, dd, J =7.8, 4.9 Hz), 7.27 (1H, d, J = 7.3 Hz), 6.52 (1H, d, J = 7.3 Hz), 6.06(2H, s), 2.61 (3H, s). 39 A24 B 8.19 372.1704 372.1707 C₂₃H₂₁N₃O₂(DMSO-d6) δ: 8.67 (1H, d, J = 2.4 Hz), 8.59 (1H, d, J = 4.4 Hz),8.05-7.92 (3H, m), 7.84 (1H, d, J = 8.3 Hz), 7.60-7.40 (4H, m), 6.56(1H, d, J = 6.8 Hz), 6.07 (2H, s), 3.78-3.71 (1H, m), 1.31 (6H, d, J =6.8 Hz). 40 A25 B 8.64 386.1860 386.1863 C₂₄H₂₃N₃O₂ (DMSO-d6) δ: 8.68(1H, d, J = 1.5 Hz), 8.60 (1H, dd, J = 4.9, 1.5 Hz), 8.08-8.00 (2H, m),7.94 (1H, dt, J = 7.5, 2.0 Hz), 7.65-7.56 (2H, m), 7.46 (1H, dd, J =8.0, 5.1 Hz), 7.27 (1H, d, J = 7.8 Hz), 6.44 (1H, d, J − 7.3 Hz), 6.04(2H, s), 3.78-3.71 (1H, m), 2.61 (3H, s), 1.31 (6H, d, J = 7 Hz).

TABLE 16 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 41 A26 B 8.34 390.0770390.0771 C₁₉H₁₇Cl₂N₃O₂ (DMSO-d6) δ: 8.66-8.61 (2H, m), 7.85 (1H, dt, J =8.1, 2.0 Hz), 7.52-7.46 (2H, m), 7.38 (1H, dd, J = 8.5, 2.7 Hz), 6.45(1H, d, J = 2.4 Hz), 5.56 (2H, s), 3.72-3.65 (1H, m), 1.26 (6H, d, J = 7Hz). 42 A27 A 9.64 438.0288 438.0285 C₁₉H₁₁ClF₃N₃O₂S (DMSO-d6) δ: 8.75(1H, d, J = 2.0 Hz), 8.66 (1H, dd, J = 4.9, 1.5 Hz), 8.01-7.98 (2H, m),7.51-7.46 (2H, m), 7.38 (1H, t, J = 8.0 Hz), 7.08 (1H, s), 6.08 (2H, s).43 A28 B 8.85 476.0213 476.0216 C₂₁H₁₃BrF₃N₃O₂ 44 A29 A 8.77 412.1273412.1267 C₂₂H₁₆F₃N₃O₂ 45 A30 A 9.76 412.1265 412.1267 C₂₂H₁₆F₃N₃O₂ 46A31 B 9.78 481.9778 481.9780 C₁₉H₁₁BrF₃N₃O₂S 47 A32 B 10.17 472.0548472.0549 C₂₀H₁₁F₆N₃O₂S 48 A33 B 8.72 410.0728 410.0725 C₂₁H₁₆ClN₃O₂S(DMSO-d6) δ: 8.72 (1H, d, J = 1.5 Hz), 8.64 (1H, dd, J = 4.9, 1.5 Hz),8.00-7.98 (2H, m), 7.54-7.50 (1H, m), 7.46 (1H, dd, J = 7.8, 1.0 Hz),7.37 (1H, t, J = 7.8 Hz), 6.90 (1H, s), 6.04 (2H, s), 2.77-2.70 (1H, m),1.04-0.95 (4H, m).

TABLE 17 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 49 A34 B 8.87 454.0212454.0219 C₂₁H₁₆BrN₃O₂S (DMSO-d6) δ: 8.79 (1H, d, J = 2.0 Hz), 8.71 (1H,dd, J = 4.9, 1.5 Hz), 8.11 (1H, dt, J = 8.1, 1.8 Hz), 8.04 (1H, d, J =7.8 Hz), 7.66-7.60 (2H, m), 7.29 (1H, t, J = 7.8 Hz), 7.00 (1H, s), 6.10(2H, s), 2.78-2.71 (1H, m), 1.08-0.98 (4H, m). 50 A35 B 9.25 444.0978444.0988 C₂₂H₁₆F₃N₃O₂S (DMSO-d6) δ: 8.62 (1H, d, J = 2.4 Hz), 8.56 (1H,dd, J = 4.9, 1.5 Hz), 8.38 (1H, d, J = 7.8 Hz), 7.88-7.84 (2H, m), 7.57(1H, t, J = 7.6 Hz), 7.40 (1H, dd, J = 8.3, 4.9 Hz), 7.02 (1H, s), 5.74(2H, brs), 2.80-2.73 (1H, m), 0.99-0.96 (4H, m). 51 A36 B 8.14 376.1101376.1114 C₂₁H₁₇N₃O₂S 52 A37 B 8.53 412.0878 412.0881 C₂₁H₁₈ClN₃O₂S(DMSO-d6) δ: 8.77 (1H, d, J = 2.0 Hz), 8.67 (1H, dd, J = 5.1, 1.7 Hz),8.04-7.98 (2H, m), 7.54 (1H dd, J = 8.3, 4.9 Hz), 7.46 (1H, d, J = 7.8Hz), 7.37 (1H, t, J = 7.8 Hz), 6.90 (1H, s), 6.06 (2H, s), 3.78-3.71(1H, m), 1.30 (6H, d, J = 7.3 Hz). 53 A38 B 8.66 456.0360 456.0376C₂₁H₁₈BrN₃O₂S (DMSO-d6) δ: 8.76 (1H, d, J = 2.3 Hz), 8.67 (1H, dd, J =2.4, 1.2 Hz), 8.06-8.01 (2H, m), 7.65 (1H, d, J = 7.8 Hz), 7.55 (1H, dd,J = 8.0, 5.1 Hz), 7.30 (1H, t, J = 7.8 Hz), 6.94 (1H, s), 6.11 (2H, s),3.79-3.72 (1H, m), 1.31 (6H, d, J = 6.8 Hz). 54 A39 B 9.01 446.1155446.1145 C₂₂H₁₈F₃N₃O₂S (DMSO-d6) δ: 8.70 (1H, d, J = 2.0 Hz), 8.62 (1H,dd, J = 4.9, 1.5 Hz), 8.39 (1H, d, J = 8.3 Hz), 7.96 (1H, dt, J = 7.8,2.0 Hz), 7.88 (1H, d, J = 7.3 Hz), 7.58 (1H, t, J = 7.8 Hz), 7.48 (1H,dd, J = 7.8, 4.9 Hz), 7.05 (1H, s), 5.74 (2H, brs), 3.80-3.69 (1H, m),1.31 (6H, d, J = 6.8 Hz).

TABLE 18 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 55 A40 B 8.02 378.1273378.1271 C₂₁H₁₉N₃O₂S (DMSO-d6) δ: 8.76 (1H, d, J = 1.5 Hz), 8.66 (1H,dd, J = 4.9, 1.5 Hz), 8.04-7.96 (2H, m), 7.68 (1H, t, J = 5.0 Hz), 7.51(1H, dd, J = 13.4, 1.5 Hz), 7.41-7.37 (2H, m), 6.98 (1H, s), 5.80 (2H,s), 3.75-3.68 (1H, m), 1.28 (6H, d, J = 6.8 Hz). 56 A41 A 6.85 346.0748346.0753 C₁₇H₁₃ClFN₃O₂ (DMSO-d6) δ: 8.72-8.69 (2H, m), 7.95 (1H, dt, J =7.5, 2.0 Hz), 7.58-7.50 (2H, m), 7.19 (1H, td, J = 8.5, 2.9 Hz), 6.48(1H, dd, J = 9.3, 2.4 Hz), 5.56 (2H, s), 2.51 (3H, t, J = 6.3 Hz). 57A42 A 6.90 346.0750 346.0753 C₁₇H₁₃ClFN₃O₂ (DMSO-d6) δ: 8.77 (1H, s),8.73 (1H, d, J = 4.9 Hz), 8.03 (1H dt, J = 8.3, 1.8 Hz), 7.59 (1H, dd, J= 7.8, 4.9 Hz), 7.40-7.33 (1H, m), 7.21 (1H, t, J = 9.5 Hz), 6.82 (1H,dd, J = 7.0, 1.8 Hz), 5.61 (2H, s), 2.49 (3H, s). 58 A43 A 7.85 396.0718396.0721 C₁₈H₁₃ClF₃N₃O₂ (DMSO-d6) δ: 8.69 (2H, d, J = 2.4 Hz), 7.94 (1H,dt, J = 8.0, 2.0 Hz), 7.70 (2H, q, J = 8.0 Hz), 7.55 (1H, dd, J = 8.0,5.1 Hz), 6.93 (1H, s), 5.68 (2H, s), 2.52 (3H, d, J = 4.9 Hz). 59 A44 A7.90 396.0726 396.0721 C₁₈H₁₃ClF₃N₃O₂ (DMSO-d6) δ: 8.68-8.65 (2H, m),7.88 (1H, dt, J = 7.8, 2.0 Hz), 7.80 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J= 8.8 Hz), 7.51 (1H, dd, J = 7.8, 4.9 Hz), 6.67 (1H, s), 5.70 (2H, s),2.54 (3H, s). 60 A46 A 8.42 430.0991 430.0985 C₁₉H₁₃F₆N₃O₂ (DMSO-d6) δ:8.63 (1H, dd, J = 4.9, 1.7 Hz), 8.61 (1H, d, J = 2.4 Hz), 8.01 (1H, d, J= 8.3 Hz), 7.89 (1H, d, J =8.3 Hz), 7.85 (1H, dt, J =7.8, 1.7 Hz), 7.47(1H, dd, J = 8.3, 4.9 Hz), 6.84 (1H, s), 5.78 (2H, s), 2.53 (3H, s).

TABLE 19 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 61 A47 A 9.12 404.1599404.1605 C₂₃H₂₁N₃O₄ 62 A48 B 6.09 312.1136 312.1143 C₁₇H₁₄FN₃O₂(CD3OD-d4) δ: 8.71-8.68 (2H, m), 7.98 (1H, d, J = 7.9 Hz), 7.58-7.54(1H, m), 7.31-7.27 (1H, m), 7.12-7.01 (2H, m), 6.83 (1H, t, J = 7.5 Hz),5.72 (2H, s), 2.60 (3H, s). 63 A49 B 6.23 312.1143 312.1143 C₁₇H₁₄FN₃O₂(CD3OD-d4) δ: 8.73-8.69 (2H, m), 7.99 (1H, d, J = 7.9 Hz), 7.61-7.56(1H, m), 7.34-7.28 (1H, m), 6.99 (1H, t, J = 8.2 Hz), 6.75-6.71 (2H, m),5.71 (2H, s), 2.62 (3H, s). 64 A50 B 6.26 312.1142 312.1143 C₁₇H₁₄FN₃O₂(DMSO-d6) δ: 8.73-8.69 (2H, m), 7.97 (1H, d, J = 8.1 Hz), 7.56-7.52 (1H,m), 7.14-7.09 (2H, m), 6.95-6.90 (2H, m), 5.61 (2H, s), 2.50 (3H, s). 65A51 B 6.65 328.0853 328.0847 C₁₇H₁₄ClN₃O₂ (CD3OD-d4) δ: 8.71-8.63 (2H,m), 7.93 (1H, d, J = 8.1 Hz), 7.58-7.53 (1H, m), 7.43-7.39 (1H, m),7.30-7.25 (2H, m), 6.75-6.71 (1H, m), 5.71 (2H, s), 2.64 (3H, s). 66 A52B 6.83 328.0844 328.0847 C₁₇H₁₄ClN₃O₂ (DMSO-d6) 5: 8.71-8.68 (2H, m),7.95 (1H, d, J = 8.0 Hz), 7.56-7.52 (1H, m), 7.34-7.30 (2H, m), 7.01(1H, s), 6.80 (1H, d, J = 6.4 Hz), 5.62 (2H, s), 2.50 (3H, s). 67 A53 B6.95 328.0832 328.0847 C₁₇H₁₄ClN₃O₂ (CD3OD-d4) 6: 8.85-8.78 (2H, m),8.11 (1H, d, J = 8.0 Hz), 7.72-7.68 (1H, m), 7.33 (2H, d, J = 8.3 Hz),7.02 (2H, d, J = 8.3 Hz), 5.76 (2H, s), 2.70 (3H, s). 68 A54 B 6.82372.0339 372.0342 C₁₇H₁₄BrN₃O₂ (CD3OD-d4) δ: 8.72-8.65 (2H, m), 7.94(1H, d, J = 8.0 Hz), 7.62-7.56 (2H, m), 7.32 (1H, t, J = 7.4 Hz), 7.22(1H, t, J = 7.2 Hz), 6.73 (1H, d, J = 7.6 Hz), 5.68 (2H, s), 2.66 (3H,s).

TABLE 20 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 69 A55 B 7.00 372.0339372.0342 C₁₇H₁₄BrN₃O₂ (CD3OD-d4) δ: 8.61-8.57 (2H, m), 7.89 (1H, d, J =8.0 Hz), 7.52-7.47 (1H, m), 7.33 (1H, d, J = 7.9 Hz), 7.14 (1H, t, J =7.8 Hz), 7.06 (1H, s), 6.85 (1H, d, J = 7.5 Hz), 5.73 (2H, s), 2.53 (3H,s). 70 A56 B 7.14 372.0330 372.0342 C₁₇H₁₄BrN₃O₂ (DMSO-d6) δ: 8.71-8.68(2H, m), 7.95 (1H, d, J = 7.8 Hz), 7.56-7.47 (3H, m), 6.86 (2H, d, J =8.2 Hz), 5.58 (2H, s), 2.50 (3H, s). 71 A57 B 6.50 308.1386 308.1394C₁₈H₁₇N₃O₂ (CD3OD-d4) δ: 8.72-8.67 (2H, m), 7.96 (1H, d, J = 8.0 Hz),7.58-7.54 (1H, m), 7.19-7.12 (3H, m), 6.55 (1H, d, J = 7.4 Hz), 5.65(2H, s), 2.66 (3H, s), 2.22 (3H, s). 72 A58 B 6.65 308.1383 308.1394C₁₈H₁₇N₃O₂ (CD3OD-d4) δ: 8.71-8.65 (2H, m), 7.96 (1H, d, J = 7.9 Hz),7.58-7.54 (1H, m), 7.16 (1H t, J = 7.6 Hz), 7.06 (1H d, J = 7.4 Hz),6.75 (1H, s), 6.69 (1H, d, J = 7.4 Hz), 5.67 (2H, s), 2.61 (3H, s), 2.25(3H, s). 73 A59 B 7.13 322.1552 322.1550 C₁₉H₁₉N₃O₂ (CD3OD-d4) δ:8.72-8.65 (2H, m), 7.94 (1H, d, J = 8.0 Hz), 7.57-7.54 (1H, m),7.23-7.12 (3H, m), 6.54 (1H, d, J = 7.8 Hz), 5.72 (2H, s), 2.66 (3H, s),2.56 (2H, q, J = 7.6 Hz), 1.14 (3H, t, J = 7.5 Hz). 74 A60 B 7.31362.1114 362.1111 C₁₈H₁₄F₃N₃O₂ (CD3OD-d4) δ: 8.57-8.49 (2H, m), 7.81(1H, d, J = 8.0 Hz), 7.66 (1H, d, J = 7.7 Hz), 7.53 (1H, t, J = 7.2 Hz),7.46-7.38 (2H, m), 6.73 (1H, d, J = 7.9 Hz), 5.92 (2H, s), 2.59 (3H, s).75 A61 B 7.42 362.1106 362.1111 C₁₈H₁₄F₃N₃O₂ (DMSO-d6) δ: 8.72-8.68 (2H,m), 7.97 (1H, d, J = 7.8 Hz), 7.63-7.50 (3H, m), 7.32 (1H, s), 7.13 (1H,d, J = 7.7 Hz), 5.71 (2H, s), 2.50 (3H, s).

TABLE 21 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 76 A62 B 7.47 378.1070378.1060 C₁₈H₁₄F₃N₃O₃ (CD3OD-d4) δ: 8.72-8.64 (2H, m), 7.95 (1H, d, J =7.4 Hz), 7.60-7.54 (1H, m), 7.41-7.36 (1H, m), 7.33-7.27 (2H, m), 6.83(1H, d, J = 6.8 Hz), 5.76 (2H, s), 2.64 (3H, s). 77 A63 B 7.71 378.1061378.1060 C₁₈H₁₄F₃N₃O₃ (DMSO-d6) δ: 8.72-8.68 (2H, m), 7.96 (1H, d, J =7.8 Hz), 7.56-7.50 (1H, m), 7.43 (1H, t, J = 8.0 Hz), 7.23 (1H, d, J =8.4 Hz), 6.93-6.87 (2H, m), 5.67 (2H, s), 2.50 (3H, s). 78 A64 B 5.73319.1198 319.1190 C₁₈H₁₄N₄O₂ (DMSO-d6) δ: 8.76-8.67 (2H, m), 8.00 (1H,d, J = 7.9 Hz), 7.83 (1H, d, J = 7.6 Hz), 7.62 (1H, t, J = 7.7 Hz),7.56-7.52 (1H, m), 7.44 (1H, t, J = 7.7 Hz), 6.76 (1H, d, J = 8.0 Hz),5.75 (2H, s), 2.50 (3H, s). 79 A65 B 5.71 319.1191 319.1190 C₁₈H₁₄N₄O₂(DMSO-d6) δ: 8.61-8.56 (2H, m), 7.82 (1H, d, J = 8.0 Hz), 7.66 (1H, d, J= 7.7 Hz), 7.49-7.40 (2H, m), 7.31 (1H, s), 7.15 (1H, d, J = 8.2 Hz),5.84 (2H, s), 2.44 (3H, s). 80 A66 A 8.78 394.1543 394.1550 C₂₅H₁₉N₃O₂81 A67 A 8.96 412.0598 412.0614 C₂₁H₁₅Cl₂N₃O₂ 82 A68 B 7.64 362.0456362.0458 C₁₇H₁₃Cl₂N₃O₂ (CD3OD-d4) δ: 8.73-8.69 (2H, m), 7.99 (1H, d, J =8.0 Hz), 7.62-7.58 (1H, m), 7.45 (1H, d, J = 8.3 Hz), 7.16 (1H, s), 6.86(1H, d, J = 8.3 Hz), 5.66 (2H, s), 2.61 (3H, s). 83 A69 B 6.88 362.0468362.0458 C₁₇H₁₃Cl₂N₃O₂ (DMSO-d6) δ: 8.68 (1H, s), 8.61 (1H, s), 7.94(1H, d, J = 8.0 Hz), 7.46-7.26 (4H, m), 5.57 (2H, s), 2.38 (3H, s). 84A70 B 7.52 362.0452 362.0458 C₁₇H₁₃Cl₂N₃O₂ (CD3OD-d4) δ: 8.76-8.70 (2H,m), 8.00 (1H, d, J = 8.0 Hz), 7.64-7.60 (1H, m), 7.50 (1H, d, J = 8.0Hz), 7.27 (1H, t, J = 7.9 Hz), 6.74 (1H, d, J = 7.8 Hz), 5.74 (2H, s),2.66 (3H, s).

TABLE 22 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 85 A71 B 7.72 362.0459362.0458 C₁₇H₁₃Cl₂N₃O₂ (DMSO-d6) δ: 8.70-8.69 (2H, m), 7.93 (1H, d, J =7.9 Hz), 7.56-7.50 (2H, m), 6.94 (2H, s), 5.59 (2H, s), 2.50 (3H, s). 86A72 B 6.16 346.0756 346.0753 C₁₇H₁₃ClFN₃O₂ (CD3OD-d4) δ: 8.71-8.69 (2H,m), 8.00 (1H, d, J = 7.9 Hz), 7.58-7.54 (1H, m), 7.27-7.20 (1H, m), 7.12(1H, d, J = 8.0 Hz), 6.92 (1H, t, J = 9.0 Hz), 5.98 (2H, s), 2.59 (3H,s). 87 A73 B 6.93 346.0753 346.0753 C₁₇H₁₃ClFN₃O₂ (CD3OD-d4) δ:8.85-8.66 (2H, m), 8.02 (1H, d, J = 7.9 Hz), 7.68-7.63 (1H, m), 7.27(1H, dd, J = 8.5 Hz, 2.5 Hz), 7.06 (1H, td, J = 8.4 Hz, 2.4 Hz),6.90-6.85 (1H, m), 5.72 (2H, s), 2.67 (3H, s). 88 A74 B 7.00 346.0754346.0753 C₁₇H₁₃ClFN₃O₂ (DMSO-d6) δ: 8.77-8.69 (2H, m), 8.01 (1H, d, J =8.0 Hz), 7.58-7.54 (1H, m), 7.48 (1H, t, J = 7.4 Hz), 7.13 (1H, t, J =7.9 Hz), 6.67 (1H, t, J = 7.1 Hz), 5.65 (2H, s), 2.50 (3H, s). 89 A75 B7.11 346.0749 346.0753 C₁₇H₁₃ClFN₃O₂ (DMSO-d6) δ: 8.74-8.69 (2H, m),7.97 (1H, d, J = 8.0 Hz), 7.59-7.54 (1H, m), 7.34 (1H, t, J = 8.9 Hz),7.20-7.17 (1H, m), 6.88-6.84 (1H, m), 5.59 (2H, s), 2.50 (3H, s). 90 A76B 7.15 346.0751 346.0753 C₁₇H₁₃ClFN₃O₂ (DMSO-d6) δ: 8.74-8.70 (2H, m),7.98 (1H, d, J = 8.0 Hz), 7.60-7.55 (1H, m), 7.33 (1H, d, J = 8.7 Hz),6.87 (1H, s), 6.76 (1H, d, J = 9.3 Hz), 5.61 (2H, s), 2.50 (3H, s). 91A77 B 7.63 362.0452 362.0458 C₁₇H₁₃Cl₂N₃O₂ (DMSO-d6) δ: 8.67-8.63 (2H,m), 7.87 (1H, d, J = 7.8 Hz), 7.65 (1H, s), 7.53-7.48 (1H, m), 7.37 (1H,d, J = 8.3 Hz), 6.60 (1H, d, J = 8.4 Hz), 5.55 (2H, s), 2.54 (3H, s).

TABLE 23 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 92 A78 A 7.53 342.1006342.1004 C₁₈H₁₆ClN₃O₂ (DMSO-d6) δ: 8.67 (2H, s), 7.92 (1H, d, J = 7.8Hz), 7.54-7.51 (1H, m), 7.35-7.31 (1H, m), 7.10 (1H, d, J = 7.8 Hz),6.42 (1H, s), 5.58 (2H, s), 2.51 (3H, s), 2.17 (3H, s). 93 A79 A 7.42368.0017 368.0022 C₁₅H₁₁Cl₂N₃O₂S 94 A80 A 7.40 368.0006 368.0022C₁₅H₁₁Cl₂N₃O₂S (DMSO-d6) δ: 8.80 (1H, s), 8.74 (1H, d, J = 3.9 Hz),8.08-8.04 (1H, m), 7.60 (1H, dd, J = 8.3, 4.9 Hz), 7.11 (1H, s), 5.67(2H, s), 2.45 (3H, s). 95 A81 A 7.50 350.0952 350.0958 C₁₉H₁₅N₃O₂S(DMSO-d6) δ: 8.70 (1H, d, J = 2.0 Hz), 8.61 (1H, dd, J = 4.9, 1.5 Hz),7.95 (1H, dt, J = 7.8, 2.0 Hz), 7.81-7.75 (2H, m), 7.51-7.43 (2H, m),7.31 (1H, t, J = 7.8 Hz), 6.65 (1H, d, J = 7.3 Hz), 5.82 (2H, s), 2.52(3H, s). 96 A82 B 8.51 376.1116 376.1114 C₂₁H₁₇N₃O₂S (DMSO-d6) δ:8.64-8.62 (1H, m), 8.57 (1H, dd, J = 4.9, 1.5 Hz), 7.87 (1H, d, J = 7.6Hz), 7.80-7.75 (2H, m), 7.50 (1H, d, J = 5.4 Hz), 7.44-7.38 (1H, m),7.32 (1H, t, J = 7.8 Hz), 6.61 (1H, d, J = 7.3 Hz), 5.77 (2H, s),2.74-2.67 (1H, m), 1.01-0.93 (4H, m). 97 A83 B 8.24 378.1271 378.1271C₂₁H₁₉N₃O₂S 98 A84 A 9.31 404.0664 404.0675 C₁₉H₁₂F₃N₃O₂S 99 A85 A 7.73368.0886 368.0864 C₁₉H₁₄FN₃O₂S (DMSO-d6) δ: 8.73 (1H, d, J = 2.0 Hz),8.64 (1H, dd, J = 4.9, 1.5 Hz), 7.98 (1H, dt, J = 7.8, 2.0 Hz), 7.87(1H, d, J = 5.4 Hz), 7.63 (1H, dd, J = 9.3, 2.4 Hz), 7.52-7.45 (2H, m),6.61 (1H, dd, J = 9.8, 2.0 Hz), 5.81 (2H, s), 2.52 (3H, s).

TABLE 24 HPLC Obs. Pred. Compound Retention Mass Mass Formula ExampleNo. Scheme time (M⁺ + H) (M⁺ + H) (M) ¹H-NMR 100 A86 B 8.81 394.1018394.1020 C₂₁H₁₆FN₃O₂S (DMSO-d6) δ: 12.96 (1H, s), 8.63 (1H, d, J = 2.4Hz), 8.58 (1H, dd, J = 4.9, 1.5 Hz), 7.88-7.84 (2H, m), 7.62 (1H, dd, J= 9.3, 2.4 Hz), 7.47 (1H, d, J = 5.4 Hz), 7.43-7.38 (1H, m), 6.53 (1H,dd, J = 9.3, 2.4 Hz), 5.77 (2H, s), 2.73-2.67 (1H, m), 1.01-0.92 (4H,m). 101 A87 A 6.90 376.0613 376.0614 C₁₈H₁₅Cl₂N₃O₂ (DMSO-d6) δ: 8.61(1H, d, J = 4.9 Hz), 8.35 (1H, s), 7.65 (1H, d, J = 8.3 Hz), 7.40-7.32(2H, m), 7.25 (1H, d, J = 8.3 Hz), 7.01 (1H, s), 6.34 (1H, q, J = 6.8Hz), 2.43 (3H, s), 1.95 (3H, d, J = 6.8 Hz). 102 A89 D 8.75 425.9395425.9406 C₁₆H₁₀BrCl₂N₃O₂ (DMSO-d6) δ: 13.58 (1H, s), 8.70-8.64 (2H, m),7.89 (1H, d, J = 8.0 Hz), 7.53-7.48 (2H, m), 7.39 (1H, dd, J = 8.8, 2.4Hz), 6.76 (1H, d, J =2.4 Hz), 5.57 (2H, s). 103 A92 F 9.66 442.0528442.0520 C₂₂H₁₄Cl₂FN₃O₂ (DMSO-d6) δ: 8.74 (1H, d, J = 2.0 Hz), 8.69 (1Hd, J = 4.9 Hz), 7.97 (1H d, J = 7.8 Hz), 7.66-7.38 (6H, m), 7.22 (1H,td, J = 8.5, 2.3 Hz), 6.77 (1H, d, J = 2.4 Hz), 5.61 (2H, s). 104 A93 F9.51 442.0517 442.0520 C₂₂H₁₄Cl₂FN₃O₂ (DMSO-d6) δ: 8.73 (1H, d, J = 2.0Hz), 8.68 (1H, d, J = 5.0 Hz), 7.96 (1H, d, J = 8.0 Hz), 7.85-7.79 (2H,m), 7.56-7.50 (2H, m), 7.40 (1H, dd, J = 8.8, 2.4 Hz), 7.25 (2H, t, J =8.8 Hz), 6.75 (1H, d, J = 2.4 Hz), 5.61 (2H, s) 105 A94 F 6.72 425.0559425.0567 C₂₁H₁₄Cl₂N₄O₂ (DMSO-d6) δ: 9.24 (1H, s), 8.83-8.68 (4H, m),8.00-7.88 (2H, m), 7.59-7.51 (2H, m), 7.41 (1H, dd, J = 8.8, 2.4 Hz),6.85 (1H, d, J = 2.4 Hz), 5.66 (2H, s).

TABLE 25 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 106 A95 F 6.50 425.0553425.0567 C₂₁H₁₄Cl₂N₄O₂ (DMSO-d6) δ: 8.87 (2H, d, J = 6.3 Hz), 8.75 (1H,d, J = 2.0 Hz), 8.71 (1H, dd, J = 4.9, 1.5 Hz), 8.33 (2H, d, J = 6.3Hz), 7.99-7.95 (1H, m), 7.58-7.50 (2H, m), 7.41 (1H, dd, J = 8.3, 2.4Hz), 6.88 (1H, d, J = 2.4 Hz), 5.64 (2H, s). 107 A96 F 8.07 378.0410378.0407 C₁₇H₁₃Cl₂N₃O₃ (DMSO-d6) δ: 8.66 (2H, s), 7.88 (1H, d, J = 8.0Hz), 7.53-7.48 (2H, m), 7.39 (1H, dd, J = 8.5, 2.2 Hz), 6.66 (1H, d, J =2.4 Hz), 5.55 (2H, s), 3.99 (3H, s). 108 A97 F 7.25 408.0500 408.0512C₁₈H₁₅Cl₂N₃O₄ 109 A98 F 10.06 446.0271 446.0281 C₁₈H₁₂Cl₂F₃N₃O₃ 110 A99F 10.48 454.0722 454.0720 C₂₃H₁₇Cl₂N₃O₃ 111 A100 F 10.12 458.0473458.0469 C₂₂H₁₄Cl₂FN₃O₃ 112 A101 F 8.65 373.0243 373.0254 C₁₇H₁₀Cl₂N₄O₂(DMSO-d6) δ: 8.71 (1H, d, J = 4.9 Hz), 8.67 (1H, s), 7.91 (1H, dd, J =7.8, 1.5 Hz), 7.56-7.47 (2H, m), 7.39 (1H, d, J = 8.8 Hz), 6.93 (1H, s),5.62 (2H, s). 113 A102 F 8.46 374.0443 374.0458 C₁₈H₁₃Cl₂N₃O₂ 114 A103 F8.85 414.0765 414.0771 C₂₁H₁₇Cl₂N₃O₂ 115 A104 F 8.97 394.0164 394.0178C₁₇H₁₃Cl₂N₃O₂S (DMSO-d6) δ: 13.16 (1H, s), 8.67 (2H, s), 7.89 (1H, d, J= 7.8 Hz), 7.54-7.48 (2H, m), 7.39 (1H, dd, J = 8.5, 2.2 Hz), 6.64 1H,s), 5.55 (2H, s), 2.54 (3H, s).

TABLE 26 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 116 A105 F 9.68 408.0340408.0335 C₁₈H₁₅Cl₂N₃O₂S (DMSO-d6) δ: 13.15 (1H, s), 8.67 (2H, s), 7.88(1H, d, J = 7.8 Hz), 7.53-7.48 (2H, m), 7.39 (1H, dd, J = 8.8, 2.4 Hz),6.62 (1H, s), 5.55 (2H, s), 3.15 (2H, q, J = 7.3 Hz), 1.34 (3H, t, J =7.3 Hz). 117 A106 F 6.84 410.0131 410.0127 C₁₇H₁₃Cl₂N₃O₃S 118 A107 F7.29 424.0292 424.0284 C₁₈H₁₅Cl₂N₃O₃S 119 A109 A 9.54 434.1025 434.1033C₂₁H₂₁Cl₂N₃O₃ (DMSO-d6) δ: 8.68 (2H, s), 7.94 (1H, dt, J = 8.0, 1.8 Hz),7.57-7.47 (2H, m), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 6.35 (1H, d, J = 2.0Hz), 5.63 (2H, s), 2.13-2.02 (2H, m), 1.87-1.75 (2H, m), 0.82 (6H, t, J= 7.3 Hz). 120 A112 A 8.62 465.0559 465.0549 C₂₀H₁₈Cl₂N₄O₃S (DMSO-d6) δ:8.71-8.66 (2H, m), 7.94 (1H, dt, J = 8.0, 1.8 Hz), 7.54-7.45 (2H, m),7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.73 (1H, d, J = 2.0 Hz), 5.49 (2H, s),2.90-2.83 (1H, m), 2.44 (3H, s), 1.06-0.89 (4H, m). 121 A113 A 7.62399.1484 399.1485 C₂₀H₂₂N₄O₃S (DMSO-d6) δ: 8.77 (1H, d, J = 2.4 Hz),8.70 (1H, dd, J = 4.9, 2.0 Hz), 8.02 (1H, dt, J = 8.0, 2.0 Hz),7.58-7.54 (1H, m), 7.01 (1H, d, J = 7.8 Hz), 6.94 (1H, d, J = 7.8 Hz),6.37 (1H, s), 5.41 (2H, s), 2.97 (3H, s), 2.44 (3H, s), 2.15 (3H, s),2.04 (3H, s). 122 A114 A 8.44 425.1634 425.1642 C₂₂H₂₄N₄O₃S

TABLE 27 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 123 A115 A 7.42 427.0881427.0893 C₂₀H₁₈N₄O₃S₂ (DMSO-d6) δ: 8.83 (1H, d, J = 2.0 Hz), 8.67 (1H,dd, J = 4.9, 1.5 Hz), 8.09 (1H, dt, J = 7.8, 2.0 Hz), 7.80 (1H, d, J =7.8 Hz), 7.73 (1H, d, J = 5.4 Hz), 7.56-7.51 (1H, m), 7.47 (1H, d, J =5.4 Hz), 7.31 (1H, t, J = 7.6 Hz), 6.82 (1H, d, J = 7.3 Hz), 5.71 (2H,s), 2.95 (3H, s), 2.42 (3H, s). 124 A116 A 8.21 453.1048 453.1050C₂₂H₂₀N₄O₃S₂ (DMSO-d6) δ: 8.80 (1H, d, J = 2.0 Hz), 8.65 (1H, dd, J =4.9, 2.0 Hz), 8.05 (1H, dt, J = 8.0, 1.8 Hz), 7.80 (1H, d, J = 7.8 Hz),7.73 (1H, d, J = 5.4 Hz), 7.54-7.45 (2H, m), 7.31 (1H, t, J = 7.8 Hz),6.81 (1H, d, J = 7.3 Hz), 5.71 (2H, s), 2.78-2.70 (1H, m), 2.42 (3H, s),0.97-0.77 (4H, m). 125 A117 B 8.38 453.1050 453.1050 C₂₂H₂₀N₄O₃S₂(DMSO-d6) δ: 8.74 (1H, d, J = 1.5 Hz), 8.62 (1H, dd, J = 4.9, 1.5 Hz),7.98 (1H, dt, J = 8.0, 2.0 Hz), 7.81-7.70 (2H, m), 7.49-7.43 (2H, m),7.31 (1H, t, J = 7.8 Hz), 6.80 (1H, d, J = 7.3 Hz), 5.65 (2H, s), 2.96(3H, s), 2.25-2.15 (1H, m), 0.99-0.90 (4H, m). 126 A118 B 9.15 479.1203479.1206 C₂₄H₂₂N₄O₃S₂ 127 A120 A 8.01 374.1497 374.1499 C₂₂H₁₉N₃O₃ 128A121 A 9.09 378.1002 378.1004 C₂₁H₁₆ClN₃O₂ (DMSO-d6) δ: 12.94 (1H, s),8.60 (1H, d, J = 2.4 Hz), 8.55 (1H, d, J = 2.0 Hz), 8.05-7.95 (3H, m),7.83 (1H, d, J = 8.3 Hz), 7.62-7.56 (2H, m), 7.40 (1H, t, J = 7.8 Hz),6.54 (1H, d, J = 6.8 Hz), 6.12 (2H, s), 2.53 (3H, s). 129 A122 A 7.48358.1550 358.1550 C₂₂H₁₉N₃O₂

TABLE 28 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 130 A123 A 8.34 362.1308362.1299 C₂₁H₁₆FN₃O₂ 131 A124 A 7.69 358.1552 358.1550 C₂₂H₁₉N₃O₂ 132A125 A 8.30 374.1501 374.1499 C₂₂H₁₉N₃O₃ 133 A126 A 9.81 360.1343360.1343 C₂₁H₁₇N₃O₃ 134 A127 A 6.36 359.1497 359.1503 C₂₁H₁₈N₄O₂ 135A128 A 7.78 372.1342 372.1343 C₂₂H₁₇N₃O₃ 136 A129 A 7.58 387.1813387.1816 C₂₃H₂₂N₄O₂ 137 A130 A 9.81 436.1667 436.1656 C₂₇H₂₁N₃O₃(DMSO-d6) δ: 8.45-8.41 (2H, m), 8.01-7.97 (2H, m), 7.80 (1H, d, J = 8.3Hz), 7.62-7.58 (2H, m), 7.35-7.30 (2H, m), 7.13 (2H, t, J = 7.8 Hz),7.02 (1H, t, J = 7.1 Hz), 6.83 (2H, d, J = 8.3 Hz), 6.54 (1H, d, J = 6.8Hz), 6.06 (2H, s), 2.53 (3H, s). 138 A131 A 9.59 466.1769 466.1761C₂₈H₂₃N₃O₄ (DMSO-d6) δ: 8.40 (1H, d, J = 2.0 Hz), 8.36 (1H, d, J = 2.4Hz), 8.02-7.95 (2H, m), 7.81 (1H, d, J = 8.3 Hz), 7.63-7.58 (2H, m),7.30 (1H, t, J = 7.6 Hz), 7.07-6.97 (2H, m), 6.87 (1H, dd, J = 7.8, 1.5Hz), 6.78 (1H, d, J = 8.3 Hz), 6.71-6.65 (1H, m), 6.48 (1H, d, J = 7.3Hz), 5.99 (2H, s), 3.49 (3H, s), 2.52 (3H, s). 139 A132 A 8.93 384.0581384.0568 C₁₉H₁₄ClN₃O₂S (DMSO-d6) δ: 8.68 (1H, d, J = 2.0 Hz), 8.65 (1H,d, J = 1.5 Hz), 8.06 (1H, t, J = 2.0 Hz), 7.99-7.95 (1H, m), 7.73-7.68(1H, m), 7.42-7.37 (2H, m), 7.02 (1H, s), 5.85 (2H, s), 2.51 (3H, s).

TABLE 29 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 140 A133 A 8.37 368.0856368.0864 C₁₉H₁₄FN₃O₂S (DMSO-d6) δ: 8.63 (1H, d, J = 3.5 Hz), 8.57 (1H,t, J = 1.5 Hz), 7.99-7.95 (1H, m), 7.92-7.86 (1H, m), 7.72-7.67 (1H, m),7.42-7.37 (2H, m), 6.98 (1H, s), 5.85 (2H, s), 2.50 (3.0H, s). 141 A134A 8.75 380.0369 380.0363 C₁₇H₁₂Cl₂FN₃O₂ (DMSO-d6) δ: 13.11 (1H, s), 8.67(1H, d, J = 2.4 Hz), 8.48 (1H, s), 7.89-7.84 (1H, m), 7.50 (1H, d, J =7.8 Hz), 7.39-7.35 (1H, m), 6.57 (1H, s), 5.61 (2H, s), 2.49 (3H, s).142 A135 A 9.44 396.0076 396.0068 C₁₇H₁₂Cl₃N₃O₂ (DMSO-d6) δ: 8.71 (1H,d, J = 2.4 Hz), 8.56 (1H, d, J = 2.0 Hz), 8.02 (1H, t, J = 2.0 Hz), 7.50(1H, d, J = 8.3 Hz), 7.38 (1H, dd, J = 8.8, 2.4 Hz), 6.62 (1H, d, J =2.4 Hz), 5.61 (2H, s), 2.50 (3H, s). 143 A136 A 11.07 434.0085 434.0081C₁₇H₉Cl₂F₄N₃O₂ (DMSO-d6) δ: 14.22 (1H, s), 8.73 (1H, d, J = 2.4 Hz),8.54 (1H, t, J = 1.5 Hz), 7.98-7.93 (1H, m), 7.47 (1H, d, J = 8.8 Hz),7.38 (1H, dd, J = 8.8, 2.4 Hz), 6.85 (1H, d, J = 2.4 Hz), 5.65 (2H, s).144 A137 A 11.75 449.9786 449.9785 C₁₇H₉Cl₃F₃N₃O₂ (DMSO-d6) δ: 8.76 (1H,d, J = 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz), 8.10 (1H, t, J = 2.2 Hz), 7.47(1H, d, J = 8.3 Hz), 7.38 (1H, dd, J = 8.8, 2.4 Hz), 6.87 (1H, d, J =2.4 Hz), 5.65 (2H, s). 145 A138 A 9.85 412.1271 412.1267 C₂₂H₁₆F₃N₃O₂(DMSO-d6) δ: 8.94 (1H, s), 8.89 (1H, s), 8.15 (1H, s), 8.03-7.95 (2H,m), 7.84 (1H, d, J = 8.3 Hz), 7.61-7.56 (2H, m), 7.43-7.38 (1H, m), 6.62(1H, d, J = 7.3 Hz), 6.14 (2H, s), 2.56 (3H, s). 146 A139 A 10.23430.0328 430.0331 C₁₈H₁₂Cl₂F₃N₃O₂ (DMSO-D6) δ: 13.18 (1H, s), 9.05 (1H,s), 8.91 (1H, d, J = 1.5 Hz), 8.18 (1H, s), 7.50 (1H, d, J = 8.8 Hz),7.38 (1H, dd, J = 8.8, 2.4 Hz), 6.66 (1H, d, J = 2.4 Hz), 5.63 (2H, s),2.51 (3H, s).

TABLE 30 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 147 A140 A 12.09 484.0049484.0049 C₁₈H₉Cl₂F₆N₃O₂ (DMSO-D6) δ: 9.11 (1H, s), 8.97 (1H, d, J = 2.0Hz), 8.29 (1H, s), 7.46 (1H, d, J = 8.3 Hz), 7.37 (1H, dd, J = 8.8, 2.4Hz), 6.92 (1H, d, J = 2.4 Hz), 5.66 (2H, s). 148 A141 A 9.01 402.0460402.0474 C₁₉H₁₃ClFN₃O₂S (DMSO-d6) δ: 8.66 (1H, d, J = 2.4 Hz), 8.59 (1H,t, J = 1.7 Hz), 7.98 (1H, dd, J = 7.8, 1.0 Hz), 7.95-7.91 (1H, m), 7.47(1H, dd, J = 7.8, 1.0 Hz), 7.37 (1H, t, J = 7.8 Hz), 6.91 (1H, s), 6.10(2H, s), 2.52 (3H, s). 149 A142 A 9.60 418.0180 418.0178 C₁₉H₁₃Cl₂N₃O₂S(DMSO-D6) δ: 8.67 (2H, dd, J = 12.9, 2.2 Hz), 8.10 (1H, t, J = 2.2 Hz),7.98 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.37 (1H, t, J = 8.0Hz), 6.93 (1H, s), 6.10 (2H, s), 2.52 (3H, s). 150 A143 A 10.31 452.0446452.0442 C₂₀H₁₃ClF₃N₃O₂S (DMSO-D6) δ: 13.05 (1H, s), 9.00 (2H, s), 8.27(1H, s), 7.98 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.37 (1H,t, J = 7.8 Hz), 6.96 (1H, s), 6.11 (2H, s), 2.53 (3H, s). 151 A144 B10.20 406.1318 406.1317 C₂₃H₂₀ClN₃O₂ (DMSO-D6) δ: 8.61 (1H, d, J = 2.4Hz), 8.54 (1H, d, J = 2.0 Hz), 8.04-7.96 (3H, m), 7.83 (1H, d, J = 8.3Hz), 7.62-7.56 (2H, m), 7.42 (1H, t, J = 7.6 Hz), 6.53 (1H, d, J = 7.3Hz), 6.10 (2H, s), 3.76-3.67 (1H, m), 1.30 (6H, d, J = 7 Hz). 152 A145 B10.97 404.1157 404.1160 C₂₃H₁₈ClN₃O₂ (DMSO-D6) δ: 12.96 (1H, s), 8.60(1H, d, J = 2.4 Hz), 8.50 (1H, d, J = 2.0 Hz), 8.04-7.95 (3H, m), 7.83(1H, d, J = 8.3 Hz), 7.61-7.56 (2H, m), 7.42 (1H, t, J = 7.8 Hz), 6.55(1H, d, J = 7.3 Hz), 6.09 (2H, s), 2.77-2.71 (1H, m), 1.04-0.96 (4H, m).

TABLE 31 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 153 A146 B 10.76 424.1367424.0381 C₁₉H₁₆Cl₃N₃O₂ (DMSO-D6) δ: 8.72 (1H, t, J = 2.0 Hz), 8.56 (1H,t, J = 1.7 Hz), 8.04-8.01 (1H, m), 7.50 (1H, dd, J = 8.5, 1.7 Hz), 7.38(1H, dt, J = 8.3, 1.7 Hz), 6.55 (1H, s), 5.61 (2H, s), 3.71-3.64 (1H,m), 1.26 (6H, d, J = 6.8 Hz). 154 A147 B 11.47 422.0221 422.0224C₁₉H₁₄Cl₃N₃O₂ (DMSO-d6) δ: 13.14 (1H, s), 8.70 (1H, d, J = 2.4 Hz), 8.51(1H, d, J = 2.0 Hz), 7.97 (1H, t, J = 2.0 Hz), 7.50 (1H, d, J = 8.8 Hz),7.38 (1H, dd, J = 8.3, 2.4 Hz), 6.61 (1H, d, J = 2.4 Hz), 5.57 (2H, s),2.73-2.66 (1H, m), 0.99-0.93 (4H, m). 155 A148 B 9.01 376.1453 376.1456C₂₂H₁₈FN₃O₂ (DMSO-D6) δ: 8.60 (1H, d, J = 2.9 Hz), 8.50 (1H, s),8.05-7.82 (4H, m), 7.62-7.55 (2H, m), 7.41 (1H, t, J = 7.8 Hz), 6.53(1H, d, J = 6.8 Hz), 6.12 (2H, s), 2.97 (2H, q, J = 7.5 Hz), 1.27 (3H,t, J = 7.6 Hz). 156 A149 B 9.61 392.1156 392.1160 C₂₂H₁₈ClN₃O₂ (DMSO-D6)δ: 8.62 (1H, d, J = 1.5 Hz), 8.56 (1H, s), 8.05-7.95 (3H, m), 7.83 (1H,d, J = 8.3 Hz), 7.62-7.56 (2H, m), 7.41 (1H, t, J = 7.8 Hz), 6.55 (1H,d, J = 7.3 Hz), 6.12 (2H, s), 2.97 (2H, q, J = 7.5 Hz), 1.27 (3H, t, J =7.3 Hz). 157 A150 B 9.34 394.0528 394.0520 C₁₈H₁₄Cl₂FN₃O₂ (DMSO-D6) δ:8.69 (1H, d, J = 2.7 Hz), 8.50 (1H, t, J = 1.8 Hz), 7.89 (1H, dt, J =9.4, 1.8 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.37 (1H, dd, J = 8.8, 2.7 Hz),6.56 (1H, d, J = 2.7 Hz), 5.62 (2H, s), 2.92 (2H, q, J = 7.5 Hz), 1.23(3H, t, J = 7.6 Hz). 158 A151 B 10.04 410.0229 410.0224 C₁₈H₁₄Cl₃N₃O₂(DMSO-d6) δ: 8.73 (1H, d, J = 2.4 Hz), 8.57 (1H, d, J = 2.0 Hz), 8.05(1H, t, J = 2.2 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.8,2.4 Hz), 6.61 (1H, d, J = 2.4 Hz), 5.62 (2H, s), 2.93 (2H, q, J = 7.5Hz), 1.23 (3H, t, J = 7.3 Hz).

TABLE 32 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 159 A152 B 9.57 390.1601390.1612 C₂₃H₂₀FN₃O₂ (DMSO-d6) δ: 8.59 (1H, d, J = 2.4 Hz), 8.49 (1H, t,J = 1.7 Hz), 8.05-7.95 (2H, m), 7.86-7.80 (2H, m), 7.63-7.56 (2H, m),7.41 (1H, t, J = 7.6 Hz), 6.52 (1H, d, J = 7.3 Hz), 6.11 (2H, s),3.76-3.69 (1H, m), 1.30 (6H, d, J = 6.8 Hz). 160 A153 B 10.23 388.1446388.1456 C₂₃H₁₈FN₃O₂ (DMSO-d6) δ: 12.97 (1H, s), 8.57 (1H, d, J = 2.9Hz), 8.44 (1H, t, J = 1.7 Hz), 8.06-7.94 (2H, m), 7.85-7.76 (2H, m),7.62-7.56 (2H, m), 7.42 (1H, t, J = 7.8 Hz), 6.53 (1H, d, J = 6.8 Hz),6.09 (2H, s), 2.77-2.71 (1H, m), 1.05-0.95 (4H, m). 161 A154 B 10.01408.0675 408.0676 C₁₉H₁₆Cl₂FN₃O₂ (DMSO-d6) δ: 13.18 (1H, s), 8.68 (1H,d, J = 2.4 Hz), 8.48 (1H, s), 7.86 (1H, dt, J = 9.6, 2.1 Hz), 7.50 (1H,d, J = 8.8 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 6.49 (1H, d, J = 2.4Hz), 5.60 (2H, s), 3.72-3.63 (1H, m), 1.26 (6H, d, J = 6.8 Hz). 162 A155B 10.65 406.0509 406.0520 C₁₉H₁₄Cl₂FN₃O₂ (DMSO-d6) δ: 8.67 (1H, d, J =2.9 Hz), 8.44 (1H, t, J = 2.1 Hz), 7.82 (1H, dt, J = 9.4, 2.1 Hz), 7.50(1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.8, 2.4 Hz), 6.58 (1H, d, J =2.4 Hz), 5.58 (2H, s), 2.73-2.66 (1H, m), 0.99-0.94 (4H, m). 163 A156 A7.67 376.0598 376.0614 C₁₈H₁₅Cl₂N₃O₂ (DMSO-d6) δ: 8.48 (1H, d, J = 2.4Hz), 8.37 (1H, d, J = 2.4 Hz), 7.70 (1H, t, J = 2.4 Hz), 7.51 (1H, d, J= 8.3 Hz), 7.39 (1H, dd, J = 8.3, 2.4 Hz), 6.55 (1H, d, J = 2.4 Hz),5.57 (2H, s), 2.49 (3H, s), 2.28 (3H, s). 164 A157 A 8.03 392.0556392.0563 C₁₈H₁₅Cl₂N₃O₃ (DMSO-d6) δ: 8.35 (1H, d, J = 2.9 Hz), 8.17 (1H,d, J = 1.5 Hz), 7.51 (1H, d, J = 8.8 Hz), 7.39-7.37 (2H, m), 6.55 (1H,d, J = 2.4 Hz), 5.57 (2H, s), 3.75 (3H, s), 2.49 (3H, s).

TABLE 33 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 165 A158 A 8.95 387.0414387.0410 C₁₈H₁₂Cl₂N₄O₂ (DMSO-d6) δ: 8.37 (1H, d, J = 4.9 Hz), 8.08 (1H,t, J = 8.5 Hz), 7.47 (1H, t, J = 6.1 Hz), 7.43 (1H, d, J = 8.8 Hz), 7.34(1H, dd, J = 8.3, 2.4 Hz), 6.54 (1H, d, J = 2.4 Hz), 5.48 (2H, s), 2.49(3H, s). 166 A159 A 7.40 376.0605 376.0614 C₁₈H₁₅Cl₂N₃O₂ (DMSO-d6) δ:8.39 (1H, d, J = 2.0 Hz), 7.65 (1H, dd, J = 8.0, 2.2 Hz), 7.47 (1H, d, J= 8.8 Hz), 7.34 (1H, dd, J = 8.3, 2.4 Hz), 7.27 (1H, d, J = 8.3 Hz),6.42 (1H, d, J = 2.4 Hz), 5.74 (2H, s), 2.48 (3H, s), 2.45 (3H, s). 167A160 A 10.21 380.0368 380.0363 C₁₇H₁₂Cl₂FN₃O₂ (DMSO-d6) δ: 9.09 (1H, d,J = 2.0 Hz), 8.89 (1H, d, J = 2.0 Hz), 8.44 (1H, t, J = 2.0 Hz), 7.48(1H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 6.61 (1H, d, J =2.4 Hz), 5.62 (2H, s), 2.49 (3H, s). 168 A161 A 8.60 392.0558 392.0563C₁₈H₁₅Cl₂N₃O₃ (DMSO-d6) δ: 8.16 (1H, d, J = 2.0 Hz), 7.74 (1H, dd, J =8.3, 2.4 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 8.8, 2.4 Hz),6.87 (1H, d, J = 8.8 Hz), 6.47 (1H, d, J = 2.4 Hz), 5.62 (2H, s), 3.85(3H, s), 2.47 (3H, s). 169 A162 A 8.32 392.0558 392.0563 C₁₈H₁₅Cl₂N₃O₃(DMSO-d6) δ: 8.27 (1H, dd, J = 4.9, 2.0 Hz), 7.74 (1H, dd, J = 7.3, 2.0Hz), 7.41 (1H, d, J = 8.3 Hz), 7.32 (1H, dd, J = 8.5, 2.7 Hz), 7.07 (1H,dd, J = 7.3, 4.9 Hz), 6.54 (1H, d, J = 2.4 Hz), 5.35 (2H, s), 3.63 (3H,s), 2.46 (3H, s). 170 A163 A 7.50 405.0881 405.0880 C₁₉H₁₈Cl₂N₄O₂ 171A164 A 9.34 396.0061 396.0068 C₁₇H₁₂Cl₃N₃O₂ 172 A165 A 8.19 440.0247440.0233 C₁₈H₁₅Cl₂N₃O₄S

TABLE 34 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 173 A166 A 8.04 431.1020431.1036 C₂₁H₂₀Cl₂N₄O₂ (DMSO-d6) δ: 7.96 (1H, d, J = 2.4 Hz), 7.82 (1H,d, J = 2.0 Hz), 7.53 (1H, d, J = 8.3 Hz), 7.40 (1H, dd, J = 8.8, 2.4Hz), 6.74 (1H, t, J = 2.2 Hz), 6.53 (1H, d, J = 2.0 Hz), 5.57 (2H, s),3.16-3.09 (4H, m), 2.49 (3H, s), 1.91-1.89 (4H, m). 174 A167 A 9.62407.0306 407.0308 C₁₇H₁₂Cl₂N₄O₄ (DMSO-d6) δ: 13.17 (1H, s), 9.41 (1H, d,J = 2.4 Hz), 9.04 (1H, d, J = 2.0 Hz), 8.54 (1H, t, J = 2.2 Hz), 7.53(1H, d, J = 8.8 Hz), 7.40 (1H, dd, J = 8.8, 2.4 Hz), 6.66 (1H, d, J =2.4 Hz), 5.63 (2H, s), 2.52 (3H, s). 175 A168 A 8.44 402.0777 402.0771C₂₀H₁₇Cl₂N₃O₂ (DMSO-d6) δ: 13.05 (1H, s), 8.49 (1H, s), 8.39 (1H, s),7.53 (1H, d, J = 8.3 Hz), 7.40 (1H, dd, J = 8.3, 2.4 Hz), 7.30 (1H, s),6.57 (1H, d, J = 2.0 Hz), 5.51 (2H, s), 2.49 (3H, s), 1.98-1.91 (1H, m),0.99-0.93 (2H, m), 0.57-0.52 (2H, m). 176 A169 C 9.75 381.9908 381.9911C₁₆H₁₀Cl₃N₃O₂ (DMSO-d6) δ: 13.20 (1H, brs), 8.71 (1H, d, J = 2.4 Hz),8.58 (1H, d, J = 2.0 Hz), 8.04 (1H, t, J = 2.2 Hz), 7.92 (1H, s), 7.50(1H, d, J = 8.3 Hz), 7.37 (1H, dd, J = 8.3, 2.4 Hz), 6.55 (1H, d, J =2.4 Hz), 5.70 (2H, s). 177 A170 A 9.92 448.0892 448.0891 C₁₉H₁₂F₇N₃O₂(DMSO-d6) δ: 8.65 (1H, d, J = 2.4 Hz), 8.42 (1H, s), 8.00 (1H, d, J =8.3 Hz), 7.91-7.84 (2H, m), 6.83 (1H, s), 5.83 (2H, s), 2.52 (3H, s).178 A171 C 9.03 366.0205 366.0207 C₁₆H₁₀Cl₂FN₃O₂ (DMSO-d6) δ: 8.68 (1H,d, J = 2.9 Hz), 8.51 (1H, d, J = 2.5 Hz), 7.92-7.88 (2H, m), 7.50 (1H,d, J = 8.3 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 6.52 (1H, s), 5.71 (2H,s).

TABLE 35 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 179 A172 A 6.93 378.0404378.0407 C₁₇H₁₃Cl₂N₃O₃ (DMSO-d6) δ: 10.51 (1H, s), 8.24 (1H, d, J = 2.4Hz), 8.12 (1H, d, J = 1.5 Hz), 7.53 (1H, d, J = 8.8 Hz), 7.40 (1H, dd, J= 8.5, 2.2 Hz), 7.27 (1H, t, J = 2.0 Hz), 6.63 (1 H, d, J = 2.0 Hz),5.54 (2H, s), 2.51 (3H, s). 180 A173 A 10.55 464.0596 464.0595C₁₉H₁₂ClF₆N₃O₂ (DMSO-d6) δ: 8.69 (1H, d, J = 2.4 Hz), 8.49 (1H, d, J =1.5 Hz), 8.03-7.99 (2H, m), 7.89 (1H, d, J = 8.3 Hz), 6.84 (1H, s), 5.83(2H, s), 2.52 (3H, s). 181 A174 A 8.63 406.0728 406.0720 C₁₉H₁₇Cl₂N₃O₃(DMSO-d6) δ: 8.36 (1H, d, J = 2.4 Hz), 8.20 (1H, s), 7.51 (1H, d, J =8.8 Hz), 7.43-7.37 (2H, m), 6.62 (1H, d, J = 2.0 Hz), 5.58 (2H, s), 4.02(2H, q, J = 7.0 Hz), 2.51 (3H, s), 1.28 (3H, t, J = 6.8 Hz). 182 A175 A9.09 420.0891 420.0876 C₂₀H₁₉Cl₂N₃O₃ (DMSO-d6) δ: 8.34 (1H, d, J = 2.4Hz), 8.22 (1H, d, J = 1.5 Hz), 7.51 (1H, d, J = 8.8 Hz), 7.41-7.38 (2H,m), 6.67 (1H, d, J = 2.0 Hz), 5.58 (2H, s), 4.55-4.49 (1H, m), 2.52 (3H,s), 1.20 (6H, d, J = 6.3 Hz). 183 A176 A 9.67 438.0773 438.0771C₂₃H₁₇Cl₂N₃O₂ (DMSO-d6) δ: 9.00 (1H, d, J = 2.4 Hz), 8.65 (1H, d, J =1.5 Hz), 8.07 (1H, t, J = 2.2 Hz), 7.62 (2H, d, J = 7.3 Hz), 7.53-7.38(5H, m), 6.72 (1H, d, J = 2.4 Hz), 5.64 (2H, s), 2.54 (3H, s). 184 A177A 9.61 439.9573 439.9563 C₁₇H₁₂BrCl₂N₃O₂ (DMSO-d6) δ: 8.78 (1H, d, J =2.4 Hz), 8.58 (1H, d, J = 2.0 Hz), 8.13-8.10 (1H, m), 7.50 (1H, d, J =8.3 Hz), 7.38 (1H, dd, J = 8.8, 2.4 Hz), 6.61 (1H, d, J = 2.0 Hz), 5.60(2H, s), 2.49 (3H, s). 185 A178 A 8.26 340.1457 340.1456 C₁₉H₁₈FN₃O₂(DMSO-d6) δ: 8.66 (1H, d, J = 2.4 Hz), 8.52 (1H, s), 7.82 (1H, d, J =9.8 Hz), 7.05 (1H, d, J = 7.3 Hz), 6.93 (1H, d, J = 7.3 Hz), 6.18 (1H,s), 5.55 (2H, s), 2.50 (3H, s), 2.14 (3H, s), 2.12 (3H, s).

TABLE 36 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 186 A179 A 8.86 356.1165356.1160 C₁₉H₁₈ClN₃O₂ (DMSO-d6) δ: 8.68 (1H, d, J = 2.4 Hz), 8.57 (1H,d, J = 1.5 Hz), 7.97 (1H, t, J = 2.2 Hz), 7.05 (1H, d, J = 7.8 Hz), 6.93(1H, d, J = 7.8 Hz), 6.19 (1H, s), 5.55 (2H, s), 2.50 (3H, s), 2.13 (3H,s), 2.12 (3H, s). 187 A180 A 7.48 336.1699 336.1707 C₂₀H₂₁N₃O₂ (DMSO-d6)δ: 8.54 (1H, s), 8.48 (1H, s), 7.82 (1H, s), 7.05 (1H, d, J = 7.3 Hz),6.94 (1H, d, J = 7.3 Hz), 6.23 (1H, s), 5.53 (2H, s), 2.52 (3H, s), 2.29(3H, s), 2.13 (6H, s). 188 A181 A 8.22 390.0770 390.0771 C₁₉H₁₇Cl₂N₃O₂(DMSO-d6) δ: 8.58 (1H, d, J = 2.0 Hz), 8.51 (1H, d, J = 2.0 Hz), 7.76(1H, t, J = 2.0 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.40 (1H, dd, J = 8.8,2.4 Hz), 6.67 (1H, d, J = 2.4 Hz), 5.58 (2H, s), 2.63 (2H, q, J = 7.5Hz), 2.52 (3H, s), 1.10 (3H, t, J = 7.6 Hz). 189 A182 A 8.75 408.0345408.0335 C₁₈H₁₅Cl₂N₃O₂S (DMSO-d6) δ: 8.54 (1H, d, J = 2.4 Hz), 8.37 (1H,d, J = 2.0 Hz), 7.64 (1H, t, J = 2.0 Hz), 7.52 (1H, d, J = 8.8 Hz), 7.40(1H, dd, J = 8.8, 2.4 Hz), 6.64 (1H, d, J = 2.4 Hz), 5.56 (2H, s), 2.51(3H, s), 2.39 (3H, s). 190 A183 A 8.16 404.0567 404.0563 C₁₉H₁₅Cl₂N₃O₃(DMSO-d6) δ: 13.11 (1H, s), 9.15 (1H, d, J = 2.0 Hz), 8.86 (1H, d, J =2.0 Hz), 8.22 (1H, t, J = 2.0 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.40 (1H,dd, J = 8.3, 2.4 Hz), 6.63 (1H, d, J = 2.4 Hz), 5.59 (2H, s), 2.56 (3H,s), 2.51 (3H, s). 191 A184 A 9.92 502.0747 502.0731 C₂₄H₁₈Cl₂FN₃O₄(DMSO-d6) δ: 13.08 (1H, s), 8.54 (1H, d, J = 2.4 Hz), 8.45 (1H, d, J =1.5 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 8.3, 2.4 Hz),7.26-7.19 (1H, m), 6.92-6.83 (3H, m), 6.45 (1H, d, J = 2.4 Hz), 5.40(2H, s), 3.69 (3H, s), 2.47 (3H, s).

TABLE 37 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 192 A185 A 9.33 420.0890420.0876 C₂₀H₁₉Cl₂N₃O₃ (DMSO-d6) δ: 13.20 (1H, s), 8.37 (1H, d, J = 2.9Hz), 8.21 (1H, s), 7.52 (1H, d, J = 8.3 Hz), 7.42-7.37 (2H, m), 6.63(1H, d, J = 2.4 Hz), 5.58 (2H, s), 3.89 (2H, t, J = 6.6 Hz), 2.51 (3H,s), 1.72-1.62 (2H, m), 0.92 (3H, t, J = 7.3 Hz). 193 A186 A 6.77422.0655 422.0669 C₁₉H₁₇Cl₂N₃O₄ (DMSO-d6) δ: 8.41 (1H, d, J = 2.4 Hz),8.22 (1H, s), 7.54-7.48 (2H, m), 7.39 (1H, dd, J = 8.3, 2.0 Hz), 6.66(1H, s), 5.59 (2H, s), 4.00 (2H, t, J = 4.6 Hz), 3.68 (2H, t, J = 4.6Hz), 2.52 (3H, s). 194 A187 A 7.15 436.0820 436.0825 C₂₀H₁₉Cl₂N₃O₄(DMSO-d6) δ: 8.40 (1H, s), 8.22 (1H, d, J = 1.5 Hz), 7.53-7.47 (2H, m),7.42-7.36 (1H, m), 6.69 (1H, d, J = 2.4 Hz), 5.59 (2H, s), 4.03 (2H, t,J = 6.3 Hz), 3.51 (2H, t, J = 6.3 Hz), 2.52 (3H, s), 1.86-1.78 (2H, m).195 A188 A 9.97 434.1023 434.1033 C₂₁H₂₁Cl₂N₃O₃ (DMSO-d6) δ: 13.06 (1H,s), 8.34 (1H, s), 8.19 (1H, s), 7.52 (1H, d, J = 8.3 Hz), 7.40 (1H, d, J= 8.3 Hz), 7.31 (1H, s), 6.59 (1H, s), 5.56 (2H, s), 3.66 (2H, d, J =6.3 Hz), 2.49 (3H, s), 1.99-1.90 (1H, m), 0.91 (6H, d, J = 6.3 Hz). 196A189 A 11.35 474.1351 474.1346 C₂₄H₂₅Cl₂N₃O₃ (DMSO-d6) δ: 8.35 (1H, s),8.21 (1H, s), 7.52 (1H, d, J = 8.3 Hz), 7.40 (1H, dd, J = 8.8, 2.4 Hz),7.33 (1H, s), 6.64 (1H, d, J = 2.0 Hz), 5.56 (2H, s), 3.69 (2H, d, J =6.3 Hz), 2.51 (3H, s), 1.75-1.60 (6H, m), 1.26-1.11 (3H, m), 1.02-0.90(2H, m). 197 A190 A 9.98 468.0860 468.0876 C₂₄H₁₉Cl₂N₃O₃ (DMSO-d6) δ:13.12 (1H, s), 8.50 (1H, s), 8.30 (1H, s), 7.50 (2H, d, J = 8.8 Hz),7.40-7.31 (6H, m), 6.57 (1H, d, J = 2.4 Hz), 5.55 (2H, s), 5.11 (2H, s),2.49 (3H, s).

TABLE 38 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 198 A192 E 8.01 439.0492439.0490 C₁₉H₁₇Cl₃N₄O₂ 199 A194 E 8.38 465.0640 465.0646 C₂₁H₁₉Cl₃N₄O₂(DMSO-d6) δ: 10.13 (1H, s), 8.76 (1H, d, J = 2.4 Hz), 8.62 (1H, d, J =1.5 Hz), 8.10 (1H, t, J = 2.2 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.40 (1H,dd, J = 8.8, 2.4 Hz), 6.70 (1H, d, J = 2.4 Hz), 5.70 (2H, s), 4.69 (2H,d, J = 5.4 Hz), 3.62 (2H, s), 3.23 (2H, s), 2.10-1.85 (4H, m). 200 A195E 8.60 479.0782 479.0803 C₂₂H₂₁Cl₃N₄O₂ (DMSO-d6) δ: 9.81 (1H, s), 8.77(1H, d, J = 2.4 Hz), 8.62 (1H, d, J = 1.5 Hz), 8.10 (1H, t, J = 2.2 Hz),7.51 (1H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.3, 2.4 Hz), 6.72 (1H, d, J= 2.4 Hz), 5.69 (2H, s), 4.58 (2H, d, J = 3.9 Hz), 3.52 (2H, d, J = 11.7Hz), 3.12-3.00 (2H, m), 1.89-1.64 (5H, m), 1.47-1.35 (1H, m). 201 A196 E8.16 481.0583 481.0596 C₂₁H₁₉Cl₃N₄O₃ (DMSO-d6) δ: 8.76 (1H, d, J = 2.0Hz), 8.61 (1H, d, J = 2.0 Hz), 8.08 (1H, t, J = 2.0 Hz), 7.51 (1H, d, J= 8.3 Hz), 7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.73 (1H, d, J = 2.4 Hz),5.70 (2H, s), 4.62 (2H, s), 3.85 (4H, s), 3.35 (4H, s). 202 A197 E 7.52494.0897 494.0912 C₂₂H₂₂Cl₃N₅O₂ (DMSO-d6) δ: 8.75 (1H, d, J = 2.4 Hz),8.60 (1H, d, J = 1.5 Hz), 8.05 (1H, s), 7.50 (1H, d, J = 8.3 Hz), 7.39(1H, dd, J = 8.8, 2.4 Hz), 6.64 (1H, d, J = 2.0 Hz), 5.67 (2H, s), 4.20(2H, s), 3.60-2.85 (8H, m), 2.79 (3H, s). 203 A198 E 7.90 495.0749495.0752 C₂₂H₂₁Cl₃N₄O₃ (DMSO-d6) δ: 8.76 (1H, d, J = 2.4 Hz), 8.61 (1H,d, J = 1.5 Hz), 8.08 (1H, s), 7.51 (1H, d, J = 8.3 Hz), 7.39 (1H, dd, J= 8.8, 2.4 Hz), 6.70 (1H, d, J = 2.4 Hz), 5.70 (2H, s), 4.60-4.52 (2H,m), 3.96-3.91 (1H, m), 3.70-3.62 (1H, m), 3.55-3.25 (3H, m), 3.16-3.05(1H, m), 2.00-1.50 (3H, m).

TABLE 39 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 204 A199 E 8.14 462.0289462.0286 C₂₀H₁₄Cl₃N₅O₂ (DMSO-d6) δ: 9.20 (1H, s), 8.73 (1H, d, J = 2.4Hz), 8.53 (1H, d, J = 2.0 Hz), 7.99 (1H, t, J = 2.2 Hz), 7.78 (1H, t, J= 1.7 Hz), 7.68 (1H, t, J = 1.7 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.39 (1H,dd, J = 8.5, 2.7 Hz), 6.73 (1H, d, J = 2.4 Hz), 5.73 (2H, s), 5.67 (2H,s). 205 A200 E 10.37 462.0289 462.0286 C₂₀H₁₄Cl₃N₅O₂ (DMSO-d6) δ: 13.67(1H, s), 8.71 (1H, d, J = 2.4 Hz), 8.54 (1H, d, J = 2.0 Hz), 8.01 (1H,t, J = 2.0 Hz), 7.74 (1H, d, J = 2.0 Hz), 7.50 (1H, d, J = 8.8 Hz),7.42-7.36 (2H, m), 6.63 (1H, d, J = 2.0 Hz), 6.23 (1H, t, J = 2.0 Hz),5.65 (2H, s), 5.61 (2H, s). 206 A201 E 7.75 411.0171 411.0177C₁₇H₁₃Cl₃N₄O₂ (DMSO-d6) δ: 8.76 (1H, d, J = 2.4 Hz), 8.56 (1H, d, J =1.5 Hz), 8.32 (3H, s), 8.03 (1H, t, J = 2.2 Hz), 7.53 (1H, d, J = 8.8Hz), 7.40 (1H, dd, J = 8.3, 2.4 Hz), 6.64 (1H, d, J = 2.4 Hz), 5.73 (2H,s), 4.33 (2H, s). 207 A202 E 7.83 522.1228 522.1225 C₂₄H₂₆Cl₃N₅O₂(DMSO-d6) δ: 8.74 (1H, d, J = 2.0 Hz), 8.60 (1H, d, J = 1.5 Hz), 8.05(1H, s), 7.51 (1H, d, J = 8.3 Hz), 7.39 (1H, dd, J = 8.5, 2.2 Hz), 6.64(1H, d, J = 2.0 Hz), 5.67 (2H, s), 4.19 (2H, s), 3.56-2.75 (10H, m),1.67-1.56 (2H, m), 0.92-0.86 (3H, m). 208 A203 E 8.48 558.0535 558.0531C₂₂H₂₂Cl₃N₅O₄S (DMSO-d6) δ: 8.75 (1H, d, J = 2.0 Hz), 8.60 (1H, d, J =1.5 Hz), 8.06 (1H, t, J = 1.7 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.39 (1H,dd, J = 8.8, 2.4 Hz), 6.70 (1H, d, J = 2.0 Hz), 5.71 (2H, s), 4.54 (2H,s), 3.45-3.30 (8H, m), 3.00 (3H, s).

TABLE 40 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 209 A204 E 8.72 572.0678572.0687 C₂₃H₂₄Cl₃N₅O₄S (DMSO-d6) δ: 8.75 (1H, d, J = 2.4 Hz), 8.60 (1H,d, J = 2.0 Hz), 8.07 (1H, t, J = 2.0 Hz), 7.51 (1H, d, J = 8.8 Hz), 7.39(1H, dd, J = 8.5, 2.7 Hz), 6.71 (1H, d, J = 2.4 Hz), 5.71 (2H, s), 4.59(2H, s), 3.55-3.30 (8H, m), 3.18 (2H, q, J = 7.3 Hz), 1.22 (3H, t, J =7.3 Hz). 210 A206 C 7.49 362.0458 362.0458 C₁₇H₁₃Cl₂N₃O₂ (DMSO-d6) δ:8.56 (1H, s), 8.49 (1H, s), 7.97 (1H, s), 7.84 (1H, s), 7.51 (1H, d, J =8.3 Hz), 7.39 (1H, d, J = 8.3 Hz), 6.55 (1H, s), 5.66 (2H, s), 2.32 (3H,s). 211 A208 A 8.96 412.0430 412.0426 C₁₈H₁₃Cl₂F₂N₃O₂ (DMSO-d6) δ: 13.13(1H, s), 8.84 (1H, d, J = 1.0 Hz), 8.77 (1H, d, J = 1.0 Hz), 8.04 (1H,s), 7.51 (1H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 7.15 (1H,t, J = 55.1 Hz), 6.62 (1H, d, J = 2.4 Hz), 5.60 (2H, s), 2.50 (3H, s).212 A210 A 8.43 425.9818 425.9810 C₁₇H₁₀Cl₃N₃O₄ (DMSO-d6) δ: 8.78 (1H,d, J = 2.4 Hz), 8.58 (1H, d, J = 1.5 Hz), 8.09 (1H, t, J = 2.2 Hz), 7.47(1H, d, J = 8.8 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 6.86 (1H, d, J =2.4 Hz), 5.74 (2H, s). 213 A211 E 9.37 426.0167 426.0174 C₁₈H₁₄Cl₃N₃O₃(DMSO-d6) δ: 8.73 (1H, d, J = 2.4 Hz), 8.56 (1H, d, J = 2.0 Hz), 8.03(1H, t, J = 2.0 Hz), 7.51 (1H, d, J = 8.3 Hz), 7.39 (1H, dd, J = 8.3,2.4 Hz), 6.61 (1H, d, J = 2.4 Hz), 5.62 (2H, dd, J = 25.9, 17.6 Hz),5.33 (1H, q, J = 6.5 Hz), 1.43 (3H, d, J = 6.8 Hz). 214 A212 A 10.27424.0621 424.0626 C₁₉H₁₆Cl₂FN₃O₃ (DMSO-d6) δ: 8.70 (1H, d, J = 2.4 Hz),8.49 (1H, s), 7.91-7.86 (1H, m), 7.50 (1H, d, J = 8.8 Hz), 7.38 (1H, dd,J = 8.8, 2.4 Hz), 6.58 (1H, d, J = 2.4 Hz), 5.63 (2H, s), 1.62 (6H, s).

TABLE 41 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 215 A213 A 11.11 440.0325440.0330 C₁₉H₁₆Cl₃N₃O₃ (DMSO-d6) δ: 8.74 (1H, s), 8.56 (1H, s), 8.04(1H, s), 7.50 (1H, d, J = 8.8 Hz), 7.38 (1H, dd, J = 8.5, 2.2 Hz), 6.60(1H, s), 5.63 (2H, s), 1.62 (6H, s). 216 A214 A 8.32 420.0872 420.0876C₂₀H₁₉Cl₂N₃O₃ (DMSO-d6) δ: 8.56 (1H, s), 8.45 (1H, s), 7.81 (1H, s),7.51 (1H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.5, 2.7 Hz), 6.57 (1H, d, J= 2.4 Hz), 5.60 (2H, s), 2.32 (3H, s), 1.62 (6H, s). 217 A215 A 11.73452.0927 452.0939 C₂₁H₂₀Cl₂FN₃O₃ 218 A216 A 12.59 468.0641 468.0643C₂₁H₂₀Cl₃N₃O₃ (DMSO-d6) δ: 8.74 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J =2.0 Hz), 8.07 (1H, t, J = 2.0 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.36 (1H,dd, J = 8.3, 2.4 Hz), 6.38 (1H, d, J = 2.0 Hz), 5.67 (2H, s), 2.11-2.01(2H, m), 1.86-1.76 (2H, m), 0.81 (6H, t, J = 7.3 Hz). 219 A217 A 9.60448.1202 448.1189 C₂₂H₂₃Cl₂N₃O₃ (DMSO-d6) δ: 8.57 (1H, s), 8.50 (1H, s),7.85 (1H, s), 7.49 (1H, d, J = 8.8 Hz), 7.37 (1H, dd, J = 8.3, 2.4 Hz),6.37 (1H, d, J = 2.0 Hz), 5.64 (2H, s), 2.33 (3H, s), 2.12-2.01 (2H, m),1.86-1.75 (2H, m), 0.81 (6H, t, J = 7.1 Hz). 220 A218 E 14.74 424.0015424.0017 C₁₈H₁₂Cl₃N₃O₃ (DMSO-d6) δ: 14.34 (1H, s), 8.76 (1H, d, J = 2.4Hz), 8.60 (1H, s), 8.10 (1H, s), 7.47 (1H, d, J = 8.3 Hz), 7.39 (1H, dd,J = 8.8, 2.4 Hz), 6.87 (1H, d, J = 2.0 Hz), 5.60 (2H, s), 2.64 (3H, s).221 A219 D 8.82 396.0059 396.0068 C₁₇H₁₂Cl₃N₃O₂ (DMSO-d6) δ: 13.61 (1H,s), 8.53 (1H, d, J = 1.5 Hz), 8.42 (1H, d, J = 2.0 Hz), 7.77 (1H, s),7.51 (1H, d, J = 8.8 Hz), 7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.78 (1H, d, J= 2.4 Hz), 5.58 (2H, s), 2.30 (3H, s).

TABLE 42 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 222 A220 D 11.28 415.9532415.9522 C₁₆H₉Cl₄N₃O₂ (DMSO-d6) δ: 13.67 (1H, s), 8.75 (1H, d, J = 2.4Hz), 8.59 (1H, d, J = 1.5 Hz), 8.07 (1H, t, J = 2.2 Hz), 7.49 (1H, d, J= 8.3 Hz), 7.39 (1H, dd, J = 8.8, 2.4 Hz), 6.85 (1H, d, J = 2.4 Hz),5.62 (2H, s). 223 A222 A 8.02 394.0528 394.0520 C₁₈H₁₄Cl₂FN₃O₂ (DMSO-d6)δ: 8.61 (1H, d, J = 2.9 Hz), 8.21 (1H, s), 7.47 (1H, dt, J = 8.9, 2.2Hz), 7.36 (1H, d, J = 8.8 Hz), 7.27 (1H, dd, J = 8.3, 2.4 Hz), 7.02 (1H,d, J = 2.4 Hz), 6.36 (1H, q, J = 6.8 Hz), 2.40 (3H, s), 1.93 (3H, d, J =6.8 Hz). 224 A223 A 8.60 410.0216 410.0224 C₁₈H₁₄Cl₃N₃O₂ (DMSO-d6) δ:8.63 (1H, d, J = 2.0 Hz), 8.32 (1H, s), 7.50 (1H, s), 7.37 (1H, d, J =8.3 Hz), 7.28 (1H, dd, J = 8.5, 2.2 Hz), 6.96 (1H, d, J = 2.4 Hz), 6.39(1H, q, J = 6.8 Hz), 2.40 (3H, s), 1.90 (3H, d, J = 6.8 Hz). 225 A224 A7.25 390.0774 390.0771 C₁₉H₁₇Cl₂N₃O₂ (DMSO-d6) δ: 8.44 (1H, s), 8.22(1H, s), 7.35 (1H, d, J = 8.3 Hz), 7.29-7.22 (2H, m), 6.94 (1H, s), 6.39(1H, q, J = 6.8 Hz), 2.41 (3H, s), 2.22 (3H, s), 1.92 (3H, d, J = 6.8Hz). 226 A225 A 8.91 385.9922 385.9928 C₁₅H₁₀Cl₂FN₃O₂S 227 A226 A 9.66401.9637 401.9632 C₁₅H₁₀Cl₃N₃O₂S 228 A227 A 7.75 382.0170 382.0178C₁₆H₁₃Cl₂N₃O₂S 229 A228 A 8.99 385.9929 385.9928 C₁₅H₁₀Cl₂FN₃O₂S(DMSO-d6) δ: 8.74 (1H, d, J = 2.4 Hz), 8.63 (1H, s), 8.05-8.00 (1H, m),7.10 (1H, s), 5.69 (2H, s), 2.43 (3H, s). 230 A229 A 9.74 401.9641401.9632 C₁₅H₁₀Cl₃N₃O₂S (DMSO-d6) δ: 8.78 (1H, d, J = 2.4 Hz), 8.70 (1H,d, J = 1.5 Hz), 8.18 (1H, t, J = 2.2 Hz), 7.11 (1H, s), 5.68 (2H, s),2.43 (3H, s). 231 A230 A 7.69 382.0169 382.0178 C₁₆H₁₃Cl₂N₃O₂S (DMSO-d6)δ: 8.62 (1H, s), 8.61 (1H, s), 7.91 (1H, s), 7.12 (1H, s), 5.67 (2H, s),2.44 (3H, s), 2.37 (3H, s).

TABLE 43 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 232 A231 A 7.84 356.1152356.1160 C₁₉H₁₈ClN₃O₂ (DMSO-d6) δ: 8.54 (1H, s), 8.46 (1H, d, J = 2.0Hz), 7.82 (1H, s), 7.33 (1H, d, J = 8.3 Hz), 7.10 (1H, d, J = 8.3 Hz),6.44 (1H, s), 5.58 (2H, s), 2.52 (3H, s), 2.30 (3H, s), 2.18 (3H, s).233 A232 A 9.50 376.0619 376.0614 C₁₈H₁₅Cl₂N₃O₂ (DMSO-d6) δ: 8.68 (1H,d, J = 2.0 Hz), 8.54 (1H, d, J = 2.0 Hz), 7.99 (1H, t, J = 2.0 Hz), 7.31(1H, d, J = 8.3 Hz), 7.08 (1H, d, J = 8.3 Hz), 6.39 (1H, s), 5.60 (2H,s), 2.49 (3H, s), 2.16 (3H, s). 234 A233 A 9.34 384.0579 384.0568C₁₉H₁₄ClN₃O₂S (DMSO-d6) δ: 13.02 (1H, s), 8.62 (1H, d, J = 2.4 Hz), 8.57(1H, d, J = 1.5 Hz), 8.00 (1H, t, J = 2.2 Hz), 7.80-7.74 (2H, m), 7.49(1H, d, J = 5.4 Hz), 7.30 (1H, t, J = 7.6 Hz), 6.65 (1H, d, J = 7.3 Hz),5.85 (2H, s), 2.50 (3H, s). 235 A234 A 8.73 368.0855 368.0864C₁₉H₁₄FN₃O₂S (DMSO-d6) δ: 8.60 (1H, d, J = 2.4 Hz), 8.52 (1H, s), 7.87(1H, dt, J = 9.8, 2.2 Hz), 7.80-7.74 (2H, m), 7.49 (1H, d, J = 5.4 Hz),7.30 (1H, t, J = 7.6 Hz), 6.65 (1H, d, J = 7.3 Hz), 5.86 (2H, s), 2.51(3H, s). 236 A235 B 10.50 412.0871 412.0881 C₂₁H₁₈ClN₃O₂S 237 A236 B11.18 410.0717 410.0725 C₂₁H₁₆ClN₃O₂S 238 A237 G 10.16 406.0147 406.0136C₁₆H₁₀Cl₃N₇ (DMSO-d6) δ: 8.72 (1H, d, J = 2.4 Hz), 8.64 (1H, d, J = 2.0Hz), 8.11 (1H, t, J = 2.2 Hz), 7.97 (1H, s), 7.49 (1H, d, J = 8.8 Hz),7.34 (1H, dd, J = 8.3, 2.4 Hz), 6.57 (1H, d, J = 2.4 Hz), 5.88 (2H, s).239 A238 A 6.96 322.1555 322.1550 C₁₉H₁₉N₃O₂ 240 A239 A 7.18 344.1396344.1394 C₂₁H₁₇N₃O₂ 241 A240 A 9.39 374.1500 374.1499 C₂₂H₁₉N₃O₃

TABLE 44 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 242 A241 A 8.03 358.1556358.1550 C₂₂H₁₉N₃O₂ 243 A242 A 9.59 378.1014 378.1004 C₂₁H₁₆ClN₃O₂ 244A243 A 8.71 344.1384 344.1394 C₂₁H₁₇N₃O₂ 245 A244 A 7.14 362.0457362.0458 C₁₇H₁₃Cl₂N₃O₂ (DMSO-d6) δ: 8.68 (2H, d, J = 5.9 Hz), 7.55-7.49(3H, m), 7.40 (1H, dd, J = 8.5, 2.7 Hz), 6.55 (1H, d, J = 2.4 Hz), 5.61(2H, s), 2.50 (3H, s). 246 A245 A 9.11 362.0454 362.0458 C₁₇H₁₃Cl₂N₃O₂(DMSO-d6) δ: 13.03 (1H, s), 8.46 (1H, d, J = 5.0 Hz), 8.16 (1H, d, J =7.8 Hz), 7.91 (1H, td, J = 7.8, 2.0 Hz), 7.51 (1H, d, J = 8.3 Hz),7.40-7.36 (1H, m), 7.31 (1H, dd, J = 8.8, 2.4 Hz), 6.35 (1H, d, J = 2.4Hz), 6.24 (2H, s), 2.50 (3H, s). 247 A246 A 9.77 392.0563 392.0563C₁₈H₁₅Cl₂N₃O₃ 248 A247 H 10.27 378.0407 378.0407 C₁₇H₁₃Cl₂N₃O₃ 249 A248H 9.01 378.0401 378.0407 C₁₇H₁₃Cl₂N₃O₃ 250 A249 H 7.27 378.0403 378.04.7C₁₇H₁₃Cl₂N₃O₃ 251 A250 H 11.96 412.0024 412.0017 C₁₇H₁₂Cl₃N₃O₃ 252 A251H 12.17 455.9492 455.9512 C₁₇H₁₂BrCl₂N₃O₃

TABLE 45 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 253 A253 H 11.33 412.0021412.0017 C₁₇H₁₂Cl₃N₃O₃ (DMSO-d6) δ: 12.93 (1H, s), 8.34 (1H, dd, J =4.6, 1.7 Hz), 8.04 (1H, dd, J = 8.0, 1.7 Hz), 7.57-7.53 (2H, m), 7.41(1H, dd, J = 8.5, 2.7 Hz), 6.78 (1H, d, J = 2.4 Hz), 5.54 (2H, s), 2.32(3H, s). 254 A254 H 11.49 455.9496 455.9512 C₁₇H₁₂BrCl₂N₃O₃ (DMSO-d6) δ:12.93 (1H, s), 8.32 (1H, dd, J = 4.6, 1.7 Hz), 8.01 (1H, dd, J = 8.0,1.7 Hz), 7.58-7.53 (2H, m), 7.41 (1H, dd, J = 8.8, 2.4 Hz), 6.80 (1H, d,J = 2.4 Hz), 5.55 (2H, s), 2.32 (3H, s). 255 A255 H 8.98 392.0564392.0563 C₁₈H₁₅Cl₂N₃O₃ (DMSO-d6) δ: 12.86 (1H, s), 8.32 (1H, d, J = 2.4Hz), 8.29 (1H, s), 7.58-7.52 (2H, m), 7.40 (1H, dd, J = 8.5, 2.7 Hz),6.75 (1H, d, J = 2.4 Hz), 5.50 (2H, s), 2.34 (3H, s), 2.30 (3H, s). 256A256 H 8.35 392.0560 392.0563 C₁₈H₁₅Cl₂N₃O₃ (DMSO-d6) δ: 8.53 (1H, s),8.38 (1H, d, J = 4.9 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.46-7.40 (2H, m),6.76 (1H, d, J = 2.4 Hz), 5.56 (2H, s), 2.31 (3H, s), 2.09 (3H, s). 257A257 H 10.95 412.0022 412.0017 C₁₇H₁₂Cl₃N₃O₃ (DMSO-d6) δ: 12.88 (1H, s),8.73 (1H, s), 8.47 (1H, d, J = 4.9 Hz), 7.72 (1H, d, J = 5.4 Hz), 7.55(1H, d, J = 8.8 Hz), 7.42 (1H, dd, J = 8.3, 2.4 Hz), 6.78 (1H, d, J =2.4 Hz), 5.55 (2H, s), 2.31 (3H, s). 258 A258 H 11.10 455.9502 455.9512C₁₇H₁₂BrCl₂N₃O₃ (DMSO-d6) δ: 12.90 (1H, s), 8.69 (1H, s), 8.36 (1H, d, J= 5.4 Hz), 7.85 (1H, d, J = 5.4 Hz), 7.55 (1H, d, J = 8.8 Hz), 7.42 (1H,dd, J = 8.3, 2.0 Hz), 6.81 (1H, d, J = 2.0 Hz), 5.55 (2H, s), 2.31 (3H,s).

TABLE 46 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 259 A259 G 7.28 356.1388356.1394 C₂₂H₁₇N₃O₂ (DMSO-d6) δ: 8.68 (1H, d, J = 2.4 Hz), 8.61 (1H, dd,J = 4.9, 1.5 Hz), 8.19 (1H, s), 8.12-8.08 (1H, m), 8.04-8.00 (1H, m),7.94-7.89 (2H, m), 7.66-7.62 (2H, m), 7.50-7.42 (2H, m), 7.26 (1H, d, J= 16.1 Hz), 6.68 (1H, d, J = 7.3 Hz), 6.47 (1H, d, J = 16.1 Hz), 6.00(2H, s). 260 A260 G 7.15 374.0454 374.0458 C₁₈H₁₃Cl₂N₃O₂ (DMSO-d6) δ:8.72-8.67 (2H, m), 8.08 (1H, s), 7.94 (1H, dt, J = 8.0, 2.0 Hz),7.58-7.54 (2H, m), 7.44 (1H, dd, J = 8.3, 2.4 Hz), 7.34 (1H, d, J = 15.6Hz), 6.72 (1H, d, J = 2.4 Hz), 6.46 (1H, d, J = 16.1 Hz), 5.53 (2H, s).261 A261 G 8.90 422.0491 422.0491 C₁₉H₁₇Cl₂N₃O₂S 262 A262 G 10.90456.0097 456.0102 C₁₉H₁₆Cl₃N₃O₂S 263 A263 G 11.08 468.0098 468.0102C₂₀H₁₆Cl₃N₃O₂S 264 A264 A 8.34 422.0484 422.0491 C₁₉H₁₇Cl₂N₃O₂S(DMSO-d6) δ: 8.61-8.56 (2H, m), 7.84 (1H, dt, J = 8.0, 2.0 Hz), 7.59(1H, s), 7.54-7.49 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 7.34 (1H, dd, J =8.8, 2.4 Hz), 6.43 (1H, d, J = 2.4 Hz), 5.47 (2H, s), 1.52 (6H, s). 265A265 A 9.87 440.0397 440.0397 C₁₉H₁₆Cl₂FN₃O₂S (DMSO-d6) δ: 8.54 (1H, d,J = 2.9 Hz), 8.36-8.34 (1H, m), 7.79-7.75 (1H, m), 7.53 (1H, s), 7.44(1H, d, J = 8.8 Hz), 7.33 (1H, dd, J = 8.3, 2.4 Hz), 6.41 (1H, d, J =2.9 Hz), 5.50 (2H, s), 1.51 (6H, s). 266 A266 A 10.41 456.0103 456.0102C₁₉H₁₆Cl₃N₃O₂S

Example 267 Production of1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid(Compound B1) (Scheme I)

(1) 2-Bromo-1H-pyrrole-5-carbaldehyde (0.53 g, 3.05 mmol) described inliterature (for example, Canadian Journal of Chemistry, 1995, 73,675-684) and 1-chloromethyl-naphthalene (0.6 mL, 4.0 mmol) weredissolved in DMF (5 mL), and potassium carbonate (0.69 g, 5 mmol) wasadded thereto, and then the mixture was heated and stirred at 80° C. for1 hour. After cooling, ethyl acetate was added and the mixture waswashed with saturated aqueous sodium chloride. The organic layer wasdried over anhydrous magnesium sulfate and was concentrated underreduced pressure. The residue obtained was purified by columnchromatography to obtain2-bromo-1-(naphthalen-1-ylmethyl)-1H-pyrrole-5-carbaldehyde (0.90 g):

¹H-NMR (CDCl₃) δ: 9.41 (1H, s), 8.04 (1H, d, J=8.3 Hz), 7.89 (1H, d,J=7.8 Hz), 7.74 (1H, d, J=8.3 Hz), 7.63-7.59 (1H, m), 7.57-7.52 (1H, m),7.29 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=4.4 Hz), 6.50 (1H, d, J=3.9 Hz),6.29 (1H, d, J=7.3 Hz), 6.20 (2H, s);

ESI-MS m/z=314 (M⁺+H).

(2) To 2-bromo-1-(naphthalen-1-ylmethyl)-1H-pyrrole-5-carbaldehyde (0.98g, 3.12 mmol), pyridin-3-ylboronic acid (0.77 g, 6.24 mmol), cesiumcarbonate (3.05 g, 9.36 mmol), and PdCl₂(dppf) (346 mg, 0.47 mmol) wereadded dioxane (24 mL) and water (2 mL), and the mixture was heated andstirred at 95° C. for 12 hours under a nitrogen atmosphere. Aftercooling, the reaction mixture was concentrated under reduced pressure.To the residue was added ethyl acetate and the organic layer was washedwith saturated aqueous sodium chloride. After being dried over anhydrousmagnesium sulfate, the organic layer was concentrated under reducedpressure. The residue obtained was purified by column chromatography toobtain1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carbaldehyde(0.89 g):

ESI-MS m/z=313 (M⁺+H).

(3) 1-(Naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carbaldehyde(0.6 g, 1.92 mmol) and 2-methyl-2-butene (2 mL, 6 mmol) were dissolvedin a mixed solvent of THF (12 mL) and 1-propanol (24 mL), and thesolution was cooled to 0° C. An aqueous solution (12 mL) of a mixture ofsodium chlorite (0.9 g, 10 mmol) and sodium dihydrogen phosphatedihydrate (1.56 g, 10 mmol) was added dropwise thereto, and the mixturewas stirred at room temperature for 17 hours. Additionally, sodiumchlorite (0.18 g, 2 mmol), sodium dihydrogen phosphate dihydrate (0.36g, 2.3 mmol), 2-methyl-2-butene (5 mL, 15 mmol), and 1-propanol (12 mL)were added and the mixture was heated and stirred at 40° C. for 29hours. After cooling, the mixture was extracted with ethyl acetate andthe organic layer was washed with saturated aqueous sodium chloride.After being dried over anhydrous magnesium sulfate, the organic layerwas concentrated under reduced pressure. The residue obtained waspurified by a conventional method to obtain1-(naphthalen-1-ylmethyl)-2-(pyridin-3-yl)-1H-pyrrole-5-carboxylic acid(0.27 g):

¹H-NMR (DMSO-d₆) δ: 12.30 (1H, s), 8.52 (1H, d, J=2.4 Hz), 8.44 (1H, dd,J=4.9, 1.5 Hz), 8.05-7.92 (2H, m), 7.78 (1H, d, J=8.3 Hz), 7.71 (1H, dt,J=7.8, 2.0 Hz), 7.58-7.53 (2H, m), 7.37 (1H, t, J=7.6 Hz), 7.31 (1H, dd,J=8.3, 4.9 Hz), 7.15 (1H, d, J=3.9 Hz), 6.54 (1H, d, J=3.9 Hz), 6.31(1H, d, J=7.3 Hz), 6.10 (2H, s);

HPLC retention time=8.04 min;

Pred. Mass=329.1285 (M⁺+H, C₂₁H₁₆N₂O₂);

Obs. Mass=329.1288 (M⁺+H).

Compounds from Compound B2 to Compound B35 were synthesized in a mannersimilar to Example 267.

TABLE 47 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 268 B2 I 8.58 343.1446 343.1441C₂₂H₁₈N₂O₂ 269 B3 I 8.61 412.9968 412.9954 C₁₉H₁₃BrN₂O₂S (DMSO-D6) δ:8.60 (1H, d, J = 1.8 Hz), 8.53 (1H, dd, J = 4.9, 1.5 Hz), 8.02-7.99 (1H,m), 7.83 (1H, dt, J = 8.0, 1.8 Hz), 7.62 (1H, dd, J = 7.8, 1.0 Hz), 7.43(1H, dd, J = 8.3, 4.9 Hz), 7.26 (1H, t, J = 7.8 Hz), 7.13 (1H, d, J =3.9 Hz), 6.53 (2H, d, J = 4.4 Hz), 6.14 (2H, s). 270 B4 I 7.62 343.1434343.1441 C₂₂H₁₈N₂O₂ (DMSO-D6) δ: 8.24 (1H, d, J = 2.0 Hz), 8.19 (1H, dd,J = 4.9, 1.5 Hz), 7.70-7.65 (2H, m), 7.52 (1H, d, J = 8.3 Hz), 7.48 (1H,dt, J = 7.6, 1.5 Hz), 7.36-7.32 (2H, m), 7.07-7.01 (3H, m), 6.30 (2H,s), 6.19 (1H, d, J = 4.4 Hz), 2.02 (3H, s). 271 B5 I 8.21 343.1428343.1441 C₂₂H₁₈N₂O₂ 272 B6 I 8.67 407.0378 407.0390 C₂₁H₁₅BrN₂O₂ 273 B7I 8.41 349.1001 349.1005 C₂₀H₁₆N₂O₂S 274 B8 I 7.90 335.0848 335.0849C₁₉H₁₄N₂O₂S (DMSO-d6) δ: 8.65 (1H, d, J = 2.0 Hz), 8.57 (1H, dd, J =4.9, 1.5 Hz), 7.96-7.92 (2H, m), 7.67-7.62 (1H, m), 7.51 (1H, dd, J =8.0, 5.1 Hz), 7.39-7.33 (2H, m), 7.11 (1H, d, J = 3.9 Hz), 6.68 (1H, s),6.51 (1H, d, J = 3.9 Hz), 5.86 (2H, s).

TABLE 48 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 275 B9 I 8.90 403.0725 403.0723C₂₀H₁₃F₃N₂O₂S (DMSO-d6) δ: 12.33 (1H, s), 8.58-8.55 (1H, m), 8.50 (1H,d, J = 3.4 Hz), 8.35 (1H, d, J = 7.8 Hz), 7.86-7.78 (2H, m), 7.54 (1H,t, J = 7.8 Hz), 7.38 (1H, dd, J = 7.8, 4.9 Hz), 7.14 (1H, d, J = 4.4Hz), 6.67 (1H, s), 6.53 (1H, d, J = 3.9 Hz), 5.81 (2H, s). 276 B10 I8.47 369.0451 369.0459 C₁₉H₁₃ClN₂O₂S (DMSO-d6) δ: 8.61 (1H, d, J = 2.4Hz), 8.53 (1H, dd, J = 4.9, 1.5 Hz), 7.95 (1H, d, J = 8.0 Hz), 7.84 (1H,dt, J = 7.8, 2.0 Hz), 7.45-7.40 (2H, m), 7.34 (1H, t, J = 7.8 Hz), 7.13(1H, d, J = 3.9 Hz), 6.54-6.49 (2H, m), 6.09 (2H, s). 277 B11 I 8.25347.0346 347.0349 C₁₇H₁₂Cl₂N₂O₂ (DMSO-d6) δ: 8.61-8.56 (2H, m), 7.82(1H, d, J = 7.8 Hz), 7.53-7.44 (2H, m), 7.33 (1H, dd, J = 8.5, 2.2 Hz),7.14 (1H, d, J = 3.9 Hz), 6.54 (1H, d, J = 3.9 Hz), 6.18 (1H, d, J = 1.5Hz), 5.63 (2H, s). 278 B12 I 7.85 307.1437 307.1441 C₁₉H₁₈N₂O₂ (DMSO-d6)δ: 8.58-8.54 (2H, m), 7.82-7.77 (1H, m), 7.49-7.45 (1H, m), 7.09 (1H,dd, J = 3.9, 1.0 Hz), 6.99 (1H, d, J = 7.3 Hz), 6.88 (1H, d, J = 7.8Hz), 6.49 (1H, d, J = 3.9 Hz), 5.96 (1H, s), 5.54 (2H, s), 2.09 (6H, s).279 B13 I 8.33 361.0520 361.0505 C₁₈H₁₄Cl₂N₂O₂ (DMSO-d6) δ: 8.47 (1H, d,J = 1.5 Hz), 8.38 (1H, d, J = 1.5 Hz), 7.73 (1H, s), 7.46 (1H, d, J =8.8 Hz), 7.33 (1H, dd, J = 8.8, 2.4 Hz), 7.13 (1H, d, J = 4.0 Hz), 6.53(1H, d, J = 4.0 Hz), 6.20 (1H, d, J = 2.4 Hz), 5.64 (2H, s), 2.30 (3H,s). 280 B14 I 11.45 365.0254 365.0254 C₁₇H₁₁Cl₂FN₂O₂ (DMSO-d6) δ: 8.57(1H, d, J = 2.4 Hz), 8.36 (1H, s), 7.78 (1H, dt, J = 9.8, 2.2 Hz), 7.45(1H, d, J = 8.8 Hz), 7.33 (1H, dd, J = 8.8, 2.4 Hz), 7.13 (1H, d, J =3.9 Hz), 6.58 (1H, d, J = 3.9 Hz), 6.19 (1H, d, J = 2.4 Hz), 5.68 (2H,s).

TABLE 49 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 281 B15 I 8.53 383.0614383.0616 C₂₀H₁₅ClN₂O₂S (DMSO-d6) δ: 8.45 (1H, d, J = 1.5 Hz), 8.43 (1H,s), 7.95 (1H, d, J = 7.8 Hz), 7.80 (1H, s), 7.44 (1H, d, J = 7.8 Hz),7.35 (1H, dd, J = 8.0, 4.0 Hz), 7.13 (1H, d, J = 4.4 Hz), 6.52-6.51 (2H,m), 6.11 (2H, s), 2.24 (3H, s). 282 B16 I 11.79 387.0364 387.0365C₁₉H₁₂ClFN₂O₂S (DMSO-d6) δ: 12.45 (1H, s), 8.53 (1H, d, J = 2.4 Hz),8.47 (1H, s), 7.95 (1H, d, J = 7.8 Hz), 7.83 (1H, dt, J = 9.1, 2.4 Hz),7.44 (1H, d, J = 7.1 Hz), 7.35 (1H, t, J = 8.0 Hz), 7.12 (1H, d, J = 7.1Hz), 6.59 (1H, d, J = 4.0 Hz), 6.51 (1H, s), 6.14 (2H, s). 283 B17 I12.28 380.9955 380.9959 C₁₇H₁₁Cl₃N₂O₂ (DMSO-d6) δ: 8.60 (1H, d, J = 2.4Hz), 8.44 (1H, d, J = 2.0 Hz), 7.91 (1H, t, J = 2.2 Hz), 7.46 (1H, d, J= 8.8 Hz), 7.33 (1H, dd, J = 8.8, 2.7 Hz), 7.13 (1H, d, J = 3.9 Hz),6.58 (1H, d, J = 3.9 Hz), 6.22 (1H, d, J = 2.4 Hz), 5.67 (2H, s). 284B18 I 12.61 403.0069 403.0069 C₁₉H₁₂Cl₂N₂O₂S (DMSO-d6) δ: 12.44 (1H, s),8.56 (1H, d, J = 2.4 Hz), 8.55 (1H, d, J = 2.4 Hz), 7.98-7.95 (2H, m),7.44 (1H, dd, J = 4.0, 2.2 Hz), 7.35 (1H, t, J = 8.0 Hz), 7.12 (1H, d, J= 4.0 Hz), 6.59 (1H, d, J = 4.0 Hz), 6.53 (1H, s), 6.13 (2H, s). 285 B19I 6.84 330.1236 330.1237 C₂₀H₁₅N₃O₂ (DMSO-d6) δ: 8.88 (1H, dd, J = 4.1,1.7 Hz), 8.60 (1H, d, J = 1.5 Hz), 8.50 (1H, dd, J = 4.9, 1.5 Hz),8.39-8.35 (1H, m), 7.92-7.82 (2H, m), 7.60-7.55 (1H, m), 7.51-7.41 (2H,m), 7.15 (1H, d, J = 4.0 Hz), 6.62-6.54 (2H, m), 6.24 (2H, s).

TABLE 50 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 286 B20 I 8.25 335.0839335.0849 C₁₉H₁₄N₂O₂S (DMSO-d6) δ: 8.57 (1H, d, J = 2.0 Hz), 8.52 (1H,dd, J = 5.1, 1.2 Hz), 7.84 (1H, d, J = 7.8 Hz), 7.76-7.72 (2H, m),7.48-7.41 (2H, m), 7.26 (1H, t, J = 7.8 Hz), 7.12 (1H, d, J = 3.9 Hz),6.52 (1H, d, J = 3.9 Hz), 6.40 (1H, d, J = 7.3 Hz), 5.85 (2H, s). 287B21 I 8.29 349.0990 349.1005 C₂₀H₁₆N₂O₂S (DMSO-d6) δ: 8.39 (2H, s), 7.75(2H, d, J = 5.9 Hz), 7.70 (1H, s), 7.47 (1H, d, J = 5.4 Hz), 7.26 (1H,t, J = 7.6 Hz), 7.11 (1H, d, J = 3.9 Hz), 6.51 (1H, d, J = 3.9 Hz), 6.42(1H, d, J = 6.8 Hz), 5.86 (2H, s), 2.18 (3H, s). 288 B22 I 11.21353.0761 353.0755 C₁₉H₁₃FN₂O₂S (DMSO-d6) δ: 12.47 (1H, s), 8.47 (1H, d,J = 2.9 Hz), 8.35 (1H, s), 7.76-7.68 (3H, m), 7.47 (1H, d, J = 5.4 Hz),7.25 (1H, t, J = 7.6 Hz), 7.12 (1H, d, J = 3.9 Hz), 6.55 (1H, d, J = 3.9Hz), 6.41 (1H, d, J = 7.3 Hz), 5.90 (2H, s). 289 B23 I 11.96 369.0464369.0459 C₁₉H₁₃ClN₂O₂S (DMSO-d6) δ: 8.50 (1H, d, J = 2.0 Hz), 8.42 (1H,s), 7.83 (1H, d, J = 1.5 Hz), 7.76-7.72 (2H, m), 7.47 (1H, d, J = 5.4Hz), 7.26 (1H, t, J = 7.6 Hz), 7.11 (1H, d, J = 4.4 Hz), 6.55 (1H, d, J= 4.4 Hz), 6.43 (1H, d, J = 7.3 Hz), 5.89 (2H, s). 290 B24 I 8.99406.1228 406.1220 C₂₂H₁₉N₃O₃S 291 B25 I 9.39 432.1387 432.1376C₂₄H₂₁N₃O₃S 292 B26 I 11.42 442.0193 442.0190 C₁₈H₁₄Cl₂FN₃O₃S 293 B27 I12.02 468.0346 468.0346 C₂₀H₁₆Cl₂FN₃O₃S

TABLE 51 HPLC Compound Retention Obs. Mass Pred. Mass Example No. Schemetime (M⁺ + H) (M⁺ + H) Formula(M) ¹H-NMR 294 B28 I 8.88 424.0303424.0284 C₁₈H₁₅Cl₂N₃O₃S 295 B29 I 12.10 457.9887 457.9894 C₁₈H₁₄Cl₃N₃O₃S296 B30 I 12.68 484.0060 484.0051 C₂₀H₁₆Cl₃N₃O₃S 297 B31 I 9.52 450.0450450.0440 C₂₀H₁₇Cl₂N₃O₃S 298 B32 I 9.50 464.0601 464.0597 C₂₁H₁₉Cl₂N₃O₃S299 B33 I 8.14 355.1439 355.1441 C₂₃H₁₈N₂O₂ (DMSO-d6) δ: 8.53 (1H, d, J= 2.0 Hz), 8.49 (1H, dd, J = 4.9, 1.5 Hz), 8.14-8.09 (1H, m), 8.02-7.98(1H, m), 7.87 (1H, d, J = 8.3 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.64-7.59(2H, m), 7.45-7.41 (2H, m), 7.28 (1H, d, J = 15.6 Hz), 7.15 (1H, d, J =3.9 Hz), 6.68 (1H, d, J = 3.9 Hz), 6.51 (1H, d, J = 6.8 Hz), 6.27 (1H,d, J = 15.6 Hz), 5.84 (2H, s). 300 B34 I 8.32 387.0658 387.0662C₂₀H₁₆Cl₂N₂O₂ (DMSO-d6) δ: 8.36 (1H, s), 8.25 (1H, s), 7.54-7.50 (2H,m), 7.40-7.34 (2H, m), 7.09 (1H, d, J = 3.9 Hz), 6.55 (1H, d, J = 4.4Hz), 6.31-6.26 (2H, m), 5.38 (2H, s), 2.26 (3H, s). 301 B35 I 11.39391.0407 391.0411 C₁₉H₁₃Cl₂FN₂O₂ (DMSO-d6) δ: 8.53 (1H, d, J = 2.9 Hz),8.35 (1H, d, J = 1.5 Hz), 7.71 (1H, dt, J = 9.9, 2.2 Hz), 7.52 (1H, d, J= 8.3 Hz), 7.39-7.35 (2H, m), 7.11 (1H, d, J = 3.9 Hz), 6.65 (1H, d, J =3.9 Hz), 6.34-6.27 (2H, m), 5.44 (2H, s).

Example 302 Test for Inhibition of Uric Acid Transport Using HumanURAT1-Expressing Cells (1) Preparation of the Test Compound

The test compound was dissolved in DMSO (produced by Sigma) to aconcentration of 20 mM and was subsequently used by diluting to desiredconcentrations.

(2) Test for Inhibition of Uric Acid Transport Using HumanURAT1-Expressing Cells

Full-length cDNA of human URAT1 (hURAT1) (produced by OriGeneTechnologies, Inc., NCBI Reference Sequence: NM 144585) was subclonedinto an expression vector, pCMV6-Kan/Neo (produced by OriGeneTechnologies, Inc.), and hURAT1 gene was transfected into humanembryonic kidney-derived cells (HEK 293 cells) by liposome method usingLipofectamine 2000 (produced by Invitrogen Corporation), whereupon HEK293 cells expressing human URAT1 gene were screened by its Geneticinresistance. By a method similar to the following method, functionalexpression of human URAT1 gene was confirmed by using transport of¹⁴C-labeled uric acid into the cells as an index.

The HEK 293 cells expressing human URAT1 were seeded in a 24-well cellculture dish to a density of 3×10⁵ cells/mL/well and were cultured inDulbecco's modified Eagle's medium (D-MEM medium) containing 10% fetalbovine serum at 37° C. for 2 days. Thereafter, the following test forinhibition of uric acid transport was performed.

After the medium was removed by aspiration from each well, the mediumwas replaced with a solution obtained by substituting NaCl in Hank'sBalanced Salt Solution (HBSS) with Na gluconate (hereinafter,HBSS/Na-gluconate) and the cells were preincubated at 37° C. for about10 minutes. HBSS/Na-gluconate was removed by aspiration and a ¹⁴C-uricacid solution that was warmed at 37° C. in advance containing variousconcentrations of the Example compound described in (1) and aradioactive ligand (¹⁴C-labeled uric acid; final concentration 25 μM)was added and an uptake reaction was carried out by incubating at 37° C.for 5 min. After the incubation, ¹⁴C-labeled uric acid solution wasremoved by aspiration and the cells were washed three times withice-cold HBSS. The HEK 293 cells expressing human URAT1 were lysed in0.2 mol/L aqueous NaOH (hereafter, the cell sample) and the cell sampleswere collected. The cell sample and a liquid scintillation liquid,ULTIMA GOLD (produced by PerkinElmer, Inc.) were mixed and theradioactivity was measured by a liquid scintillation counter (BeckmanCoulter, Inc.).

The uric acid transport rate of the Example compound at eachconcentration (% of control uptake) was calculated relative to theradioactivity (radioactivity in human URAT1 expressing HEK 293 cellswithout addition of the Example compound (DMSO addition)) showingURAT1-specific uric acid transport as 100%, and the concentration (IC₅₀)of the Example compound at which the uric acid transport rate isinhibited by 50% was determined. The results are shown in the followingtable. In addition, the symbols (*, **, and ***) in the table representthe following inhibitory activity values:

IC₅₀≦0.2 μM: *** 0.2 μM<IC₅₀≦2 μM: ** 2 μM<IC₅₀≦20 μM: *

TABLE 52 Compound Inhibitory No. Activity A1 * * A2 * * A3 * * A4 * A5 *A6 * * A7 * * A8 * * A9 * * A10 * * A11 * * A12 * A13 * * * A14 * * *A15 * * * A16 * A17 * * A18 * * * A19 * * * A22 * * A23 * * A24 * *A25 * * * A26 * * * A27 * * A28 * A30 * A31 * * A32 * A33 * * A34 * *A35 * * A36 * * A37 * * * A38 * * * A39 * * * A40 * * A41 * * A42 * *A43 * * * A44 * * A45 * * * A46 * * A47 * A48 * A49 * A50 * A51 * A52 *A53 * A54 * * A55 * * A56 * A57 * A58 * A59 * A60 * A61 * A62 * A63 *A64 * A65 * A66 * A67 * * A68 * * A70 * * A71 * * * A72 * A73 * A74 *A75 * A76 * * A77 * * A78 * * * A79 * * A80 * * A81 * * A82 * * A83 * *A84 * *

TABLE 53 Compound Inhibitory No. Activity A85 * * * A86 * * * A87 *A88 * * * A89 * * * A90 * * * A91 * * * A92 * * * A93 * * * A94 * *A95 * A96 * * * A97 * A98 * * * A99 * * * A100 * * * A101 * * * A102 * *A103 * * A104 * * * A105 * * * A106 * A107 * A108 * * * A109 * *A110 * * A111 * A112 * A115 * A116 * A117 * * A118 * * A119 * * A120 *A121 * * A124 * A125 * A130 * * A131 * A132 * * A133 * * A134 * * *A135 * * * A136 * * * A137 * * * A138 * * A139 * * * A140 * * * A141 * *A142 * * * A143 * * * A144 * * * A145 * * * A146 * * * A147 * * *A148 * * A149 * * * A150 * * * A151 * * * A152 * * A153 * * A154 * * *A155 * * * A156 * * * A157 * * * A158 * * A159 * * A160 * * A161 * *A162 * * A163 * A164 * * A165 * A166 * * * A167 * * * A168 * * *A169 * * * A170 * * A171 * * * A172 * *

TABLE 54 Compound Inhibitory No. Activity A173 * * * A174 * * * A175 * *A176 * * * A177 * * * A178 * * A179 * * * A180 * * * A181 * * *A182 * * * A183 * * * A184 * A185 * * * A186 * A187 * A188 * * *A189 * * A190 * * A191 * * * A192 * * A193 * * * A194 * * * A195 * * *A196 * * * A197 * * * A198 * A199 * * A200 * * * A201 * A202 * * *A203 * * A204 * * * A205 * * * A206 * * * A207 * * * A208 * * *A209 * * * A210 * * * A211 * * * A212 * * * A213 * * * A214 * * *A215 * * * A216 * * * A217 * * * A218 * * * A219 * * * A220 * * *A221 * * * A222 * A223 * * A224 * A225 * * * A226 * * * A227 * * *A228 * * A229 * * A230 * * A231 * * * A232 * * * A233 * * * A234 * *A235 * * * A236 * * * A237 * * * A238 * * A239 * A240 * * A241 * A242 *A243 * A244 * * A245 * * * A246 * * A247 * * A248 * * * A250 * * *A251 * * * A252 * * * A253 * * *

TABLE 55 Compound Inhibitory No. Activity A254 * * * A255 * * *A256 * * * A257 * * * A258 * * * A259 * A260 * A261 * A262 * * A263 * *A264 * A265 * A266 * * B1 * * * B2 * * * B3 * * * B4 * * B6 * * *B7 * * * B8 * * * B9 * * * B10 * * * B11 * * * B12 * * * B13 * * *B14 * * * B15 * * * B16 * * * B17 * * * B18 * * * B19 * * B20 * * *B21 * * * B22 * * * B23 * * * B24 * * * B25 * * * B26 * * * B27 * * *B28 * * * B29 * * * B30 * * * B31 * * * B32 * * * B33 * * * B34 * * *B35 * * *Test for Drug Efficacy in Cebus apella

Example 303

A test compound (3 mg/kg to 30 mg/kg) prepared by suspending in a 0.5%methylcellulose solution was administered to Cebus apella into stomachvia the nasal cavity using a disposable catheter and a syringe barrel.Blood samples were taken before administration and 30 minutes, 1 hour, 2hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration;and urine samples were collected for the time intervals of immediatelyto 4 hours after administration, from 4 hours to 8 hours afteradministration, from 8 hours to 16 hours after administration, and from16 hours to 24 hours after administration. Concentrations of uric acidand creatinine in the blood and urine samples collected were measured byan automatic analyzer (JEOL Ltd.). Uric acid and creatine were measuredusing L-type Wako UA•F (Wako Pure Chemicals Industries, Ltd.) and L-typeCreatine F (Wako Pure Chemicals Industries, Ltd.) respectively. Uricacid clearance was calculated from the uric acid concentrations in bloodand urine and, similarly, creatinine clearance was calculated from thecreatinine concentrations. From these values, the uric acid excretionrate was determined according to the following equation:

Uric acid excretion rate (%)=(uric acid clearance/creatinineclearance)×100

In the present test, the excellent uricosuric effect was confirmed forcompounds A1, A2, A7, A13, A14, A15, A19, A26, A81, A119, A121, A134,A135, A137, A139, A147, A156, A169, A233, B1, and B11.

From the above-mentioned results, it is shown that the pyridinederivative of the present invention possesses a superior uricosuriceffect.

INDUSTRIAL APPLICABILITY

The pyridine derivative of the present invention or the prodrug thereof,or the pharmaceutically acceptable salt thereof, or the solvate thereofis used as a pharmaceutical.

1-23. (canceled)
 24. A method for inhibiting URAT1, comprisingadministering to a subject an effective amount of a pyridine derivativerepresented by the following formula (I):

wherein: A represents a single bond, an oxygen atom, a sulfur atom, NH,or CH₂; R₁ represents a nitrogen atom or CH; one of X₁ to X₅ representsa nitrogen atom and the remaining four represent CR₂; R₂ eachindependently represent a hydrogen atom, an alkyl group having 1 to 6carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynylgroup having 2 to 6 carbon atoms, a halogen atom, a trifluoromethylgroup, a difluoromethyl group, a cyano group, an alkylcarbonyl grouphaving 2 to 7 carbon atoms, an alkylsulfonyl group having 1 to 6 carbonatoms, a nitro group, an amino group, a dialkylamino group having 1 to 6carbon atoms which may optionally form a ring, a formyl group, ahydroxyl group, an alkoxy group having 1 to 6 carbon atoms (which mayoptionally be substituted with one or more of a hydroxyl group, a phenylgroup, a cyclohexyl group, and a halogen atom), an alkylthio grouphaving 1 to 6 carbon atoms, a phenyl group (which may optionally besubstituted with one or more of an alkyl group having 1 to 6 carbonatoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom),or a phenoxy group (which may optionally be substituted with one or moreof an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1to 6 carbon atoms, and a halogen atom), with the proviso that when twoCR₂'s are adjacent, the two R₂'s may optionally be joined together toform a ring; R₃ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms (which may optionally be substituted with one or more of ahydroxyl group, an amino group, a dialkylamino group having 1 to 6carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkenyl group having 2 to 6carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms (which may optionally be substitutedwith one or more of a hydroxyl group and a halogen atom), analkylcarbonyl group having 2 to 7 carbon atoms, an alkylthio grouphaving 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbonatoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group,a cyano group, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), a pyridyl group(which may optionally be substituted with one or more of an alkyl grouphaving 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms,and a halogen atom), a phenoxy group (which may optionally besubstituted with one or more of an alkyl group having 1 to 6 carbonatoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom),a carboxyl group, or —CO₂R₅; R₄ represents a carboxyl group, atetrazolyl group, —CONHSO₂R₅, —CO₂R₅, or any of the followingsubstituents:

with the proviso that when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group and when R₄ is a carboxyl group,then R₃ and R₄ may optionally be fused to form a lactone ring; R₅ in R₃and R₄ each independently represents an alkyl group having 1 to 6 carbonatoms; Z represents any of the following substituents designated Z1 toZ7:

wherein: R₆ and R₇ each independently represent a hydrogen atom, ahalogen atom, an alkyl group having 1 to 6 carbon atoms, atrifluoromethyl group, a trifluoromethoxy group, or a cyano group, withthe proviso that the case where R₆ and R₇ are simultaneously hydrogenatoms is excluded; R₈ represents a hydrogen atom, a halogen atom, analkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; R₉represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6carbon atoms, or a trifluoromethyl group; R₁₀ represents a hydrogenatom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group; R₁₁ and R₁₂ each independently represent ahydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbonatoms, or a trifluoromethyl group; R₁₃ and R₁₄ each independentlyrepresent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6carbon atoms, or a trifluoromethyl group; R₁₅ represents a hydrogenatom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group; Y represents a hydrogen atom or an alkyl grouphaving 1 to 6 carbon atoms; and W represents a sulfur atom, an oxygenatom, or NR₁₆ (where R₁₆ represents a hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or a benzyl group) or the pharmaceuticallyacceptable salt thereof.
 25. A method for treatment or prevention of oneor more diseases selected from the group consisting of gout,hyperuricemia, hypertension, renal diseases such as interstitialnephritis and the like, diabetes, arteriosclerosis, and Lesch-Nyhansyndrome, comprising administering to a subject an effective amount of apyridine derivative represented by the following formula (I):

wherein: A represents a single bond, an oxygen atom, a sulfur atom, NH,or CH₂; R₁ represents a nitrogen atom or CH; one of X₁ to X₅ representsa nitrogen atom and the remaining four represent CR₂; R₂ eachindependently represent a hydrogen atom, an alkyl group having 1 to 6carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynylgroup having 2 to 6 carbon atoms, a halogen atom, a trifluoromethylgroup, a difluoromethyl group, a cyano group, an alkylcarbonyl grouphaving 2 to 7 carbon atoms, an alkylsulfonyl group having 1 to 6 carbonatoms, a nitro group, an amino group, a dialkylamino group having 1 to 6carbon atoms which may optionally form a ring, a formyl group, ahydroxyl group, an alkoxy group having 1 to 6 carbon atoms (which mayoptionally be substituted with one or more of a hydroxyl group, a phenylgroup, a cyclohexyl group, and a halogen atom), an alkylthio grouphaving 1 to 6 carbon atoms, a phenyl group (which may optionally besubstituted with one or more of an alkyl group having 1 to 6 carbonatoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom),or a phenoxy group (which may optionally be substituted with one or moreof an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1to 6 carbon atoms, and a halogen atom), with the proviso that when twoCR₂'s are adjacent, the two R₂'s may optionally be joined together toform a ring; R₃ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms (which may optionally be substituted with one or more of ahydroxyl group, an amino group, a dialkylamino group having 1 to 6carbon atoms which may optionally form a ring, an imidazole ring, apyrazole ring, a pyrrolidine ring, a piperidine ring, a morpholine ring,and a piperazine ring (which may optionally be substituted with one ormore of an alkyl group having 1 to 6 carbon atoms and an alkylsulfonylgroup having 1 to 6 carbon atoms)), an alkenyl group having 2 to 6carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms (which may optionally be substitutedwith one or more of a hydroxyl group and a halogen atom), analkylcarbonyl group having 2 to 7 carbon atoms, an alkylthio grouphaving 1 to 6 carbon atoms, an alkylsulfinyl group having 1 to 6 carbonatoms, a halogen atom, a trifluoromethyl group, a difluoromethyl group,a cyano group, a phenyl group (which may optionally be substituted withone or more of an alkyl group having 1 to 6 carbon atoms, an alkoxygroup having 1 to 6 carbon atoms, and a halogen atom), a pyridyl group(which may optionally be substituted with one or more of an alkyl grouphaving 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms,and a halogen atom), a phenoxy group (which may optionally besubstituted with one or more of an alkyl group having 1 to 6 carbonatoms, an alkoxy group having 1 to 6 carbon atoms, and a halogen atom),a carboxyl group, or —CO₂R₅; R₄ represents a carboxyl group, atetrazolyl group, —CONHSO₂R₅, —CO₂R₅, or any of the followingsubstituents:

with the proviso that when R₃ is an alkyl group having 1 to 6 carbonatoms substituted with a hydroxyl group and when R₄ is a carboxyl group,then R₃ and R₄ may optionally be fused to form a lactone ring; R₅ in R₃and R₄ each independently represents an alkyl group having 1 to 6 carbonatoms; Z represents any of the following substituents designated Z1 toZ7:

wherein: R₆ and R₇ each independently represent a hydrogen atom, ahalogen atom, an alkyl group having 1 to 6 carbon atoms, atrifluoromethyl group, a trifluoromethoxy group, or a cyano group, withthe proviso that the case where R₆ and R₇ are simultaneously hydrogenatoms is excluded; R₈ represents a hydrogen atom, a halogen atom, analkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; R₉represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6carbon atoms, or a trifluoromethyl group; R₁₀ represents a hydrogenatom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group; R₁₁ and R₁₂ each independently represent ahydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbonatoms, or a trifluoromethyl group; R₁₃ and R₁₄ each independentlyrepresent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6carbon atoms, or a trifluoromethyl group; R₁₅ represents a hydrogenatom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group; Y represents a hydrogen atom or an alkyl grouphaving 1 to 6 carbon atoms; and W represents a sulfur atom, an oxygenatom, or NR₁₆ (where R₁₆ represents a hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or a benzyl group) or the pharmaceuticallyacceptable salt thereof.
 26. A compound represented by the followingformula (II) or a pharmaceutically acceptable salt thereof, or a solvatethereof:

wherein R₁ represents a nitrogen atom; R₃ represents a hydrogen atom oran alkyl group having 1 to 6 carbon atoms; R₁₇ represents a chlorineatom, a bromine atom, or an iodine atom; R₁₈ represents a formyl groupor —CO₂R₅; R₅ represents an alkyl group having 1 to 6 carbon atoms; andZ represents any of the following substituents designated Z1 to Z7:

wherein R₆ and R₇ each independently represent a hydrogen atom, ahalogen atom, an alkyl group having 1 to 6 carbon atoms, atrifluoromethyl group, a trifluoromethoxy group, or a cyano group, withthe proviso that the case where R₆ and R₇ are simultaneously hydrogenatoms is excluded; R₈ represents a hydrogen atom, a halogen atom, analkyl group having 1 to 6 carbon atoms, or a trifluoromethyl group; R₉represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6carbon atoms, or a trifluoromethyl group; R₁₀ represents a hydrogenatom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group; R₁₁ and R₁₂ each independently represent ahydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbonatoms, or a trifluoromethyl group; R₁₃ and R₁₄ each independentlyrepresent a hydrogen atom, a halogen atom, an alkyl group having 1 to 6carbon atoms, or a trifluoromethyl group; R₁₅ represents a hydrogenatom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or atrifluoromethyl group; Y represents a hydrogen atom or an alkyl grouphaving 1 to 6 carbon atoms; and W represents a sulfur atom, an oxygenatom, or NR₁₆ (where R₁₆ represents a hydrogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or a benzyl group).
 27. A compoundrepresented by the following formula (III) or a pharmaceuticallyacceptable salt thereof, or a solvate thereof:

wherein R₃ represents a hydrogen atom or an alkyl group having 1 to 6carbon atoms; R₁₉ represents —CO₂R₅; R₅ represents an alkyl group having1 to 6 carbon atoms; and Za represents a 2,5-dichlorobenzyl group, a3,5-dichlorobenzyl group, a 2,5-dimethylbenzyl group, a2,5-bis(trifluoromethyl)benzyl group, a 2-chloro-5-methylbenzyl group, anaphthalen-1-ylmethyl group, a (2-methylnaphthalen-1-yl)methyl group, a(4-methylnaphthalen-1-yl)methyl group, a (8-methylnaphthalen-1-yl)methylgroup, a (8-bromonaphthalen-1-yl)methyl group, abenzo[b]thiophen-3-ylmethyl group, a(4-methylbenzo[b]thiophen-3-yl)methyl group, a(4-chlorobenzo[b]thiophen-3-yl)methyl group, a(4-bromobenzo[b]thiophen-3-yl)methyl group, a(4-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, a(5-methylbenzo[b]thiophen-3-yl)methyl group, a(5-chlorobenzo[b]thiophen-3-yl)methyl group, a(5-(trifluoromethyl)benzo[b]thiophen-3-yl)methyl group, abenzo[b]thiophen-7-ylmethyl group, a(5-fluorobenzo[b]thiophen-7-yl)methyl group, a(2,5-dichlorothiophen-3-yl)methyl group, a(2,4-dichlorothiophen-5-yl)methyl group, or a quinolin-8-ylmethyl group.